Trametinib

Modulation of Cell Survival Pathways

Trametinib, a highly selective, reversible, allosteric inhibitor of MEK1 and MEK2, primarily exerts its effects by blocking the catalytic activity of these kinases within the RAS-RAF-MEK-ERK pathway. This inhibition prevents the phosphorylation and activation of MEK, consequently disrupting downstream signaling crucial for cell proliferation and survival drugbank.comcancercareontario.ca. The MAPK/ERK pathway, frequently activated in cancers due to mutations in genes like RAS and BRAF, plays a vital role in regulating cellular behaviors, including proliferation, invasion, and migration mdpi.comdovepress.com.

Inhibition of MEK by this compound leads to a decrease in phosphorylated ERK (p-ERK) expression, which is associated with reduced cell proliferation spandidos-publications.com. However, the cellular response to MEK inhibition is complex, and cancer cells can employ compensatory mechanisms to maintain survival. One significant pathway involved in cell survival is the PI3K/Akt/mTOR pathway mdpi.comiiarjournals.orgoncotarget.com. Studies have shown that MEK inhibition by this compound can sometimes lead to the activation of the PI3K/Akt pathway, potentially limiting the efficacy of this compound monotherapy mdpi.comnih.gov. This feedback activation of PI3K/Akt can occur through various mechanisms, including the modulation of scaffolding proteins or feedback regulation of receptor tyrosine kinase expression, such as EGFR mdpi.comnih.gov. Hyperactivation of the PI3K/Akt pathway in response to this compound has been observed in various cancer types, including head and neck squamous cell carcinoma (HNSCC) and meningioma mdpi.comnih.gov.

Research has demonstrated that combining this compound with inhibitors targeting the PI3K/Akt/mTOR pathway can enhance anti-tumor effects and overcome resistance mechanisms mdpi.comiiarjournals.orgoncotarget.comnih.gov. For instance, in HNSCC cell lines, combining this compound with PI3K inhibitors like GDC-0941 (pictilisib) or BYL719 (alpelisib) prevented Akt hyperactivation induced by this compound and showed synergistic anti-tumor effects nih.gov. Similarly, studies in melanoma cells with acquired resistance to this compound have explored combinations with metformin, which can suppress mTOR activity, to potentially overcome resistance iiarjournals.orgoncotarget.com.

This compound also modulates apoptotic and anti-apoptotic signaling. While MEK inhibition can induce apoptosis by interfering with ERK-mediated pathways mdpi.comnih.gov, cancer cells can upregulate anti-apoptotic proteins as a survival mechanism. For example, in KRAS-mutant colorectal cancer cells, treatment with low-dose this compound was found to increase the expression of the anti-apoptotic protein Bcl-xL, contributing to drug resistance spandidos-publications.com. Combining this compound with a Bcl-xL antagonist, such as ABT263, demonstrated a synergistic effect on inducing apoptosis in these cells, associated with increased expression of the pro-apoptotic protein BIM and reduced Bcl-xL levels spandidos-publications.comuni-tuebingen.de.

Furthermore, this compound's impact on cell survival pathways extends to the modulation of necroptosis, a form of programmed cell death. Studies, such as those investigating this compound's protective effects against cisplatin-induced acute kidney injury, have shown that this compound can significantly inhibit both apoptosis and necroptosis mdpi.com. This involves reducing the expression of key proteins in the necroptotic pathway, including RIPK1, RIPK3, and p-MLKL mdpi.com.

Detailed research findings highlight the intricate interplay between the MAPK/ERK pathway and other survival pathways, such as PI3K/Akt/mTOR, in determining the response to this compound. The ability of cancer cells to activate compensatory survival mechanisms underscores the rationale for combination therapies targeting multiple pathways to enhance efficacy and overcome resistance.

Below are some data points illustrating the effects of this compound and combination therapies on cell viability and signaling proteins in various cancer cell lines:

Interactive Table 1: Effects of this compound and Combination Therapies on Cell Viability and Signaling Proteins

Interactive Table 2: Effects of this compound on Necroptosis Markers in Cisplatin-Injected Mice Kidneys

These findings underscore the multifaceted impact of this compound on cell survival pathways, highlighting its primary role in inhibiting the MAPK/ERK pathway while also revealing the complexity introduced by feedback loops and compensatory mechanisms involving pathways like PI3K/Akt/mTOR and the modulation of apoptotic and necroptotic signaling.

Suppression of Tumor Growth in BRAF V600 Mutation-Positive Tumor Xenografts

Preclinical data have demonstrated the efficacy of trametinib in inhibiting tumor growth in xenograft models harboring the BRAF V600E mutation. In a BRAFV600E-containing xenograft model of human melanoma (A375P), orally administered dabrafenib, a BRAF inhibitor, inhibited ERK activation and led to tumor growth inhibition. plos.org While this specific study focused on dabrafenib monotherapy and combination, other research highlights this compound's potent activity against BRAF-mutant models. For instance, in 8505C tumor xenografts bearing a BRAFV600E mutation, this compound alone was highly effective, resulting in sustained tumor size reductions. spandidos-publications.com Similarly, a patient-derived orthotopic xenograft (PDOX) model of BRAF-V600E-mutant melanoma showed that this compound significantly regressed tumor growth compared to the untreated control. researchgate.net This regression was observed from day 3 to day 14, with this compound demonstrating significantly greater efficacy than other tested therapies, including vemurafenib, cobimetinib, and temozolomide, by day 7. researchgate.net

Sustained Inhibition of ERK Phosphorylation in Xenograft Models

This compound's mechanism of action involves the inhibition of MEK1 and MEK2, which are directly upstream of ERK in the MAPK pathway. mims.com Preclinical studies consistently show that this compound treatment leads to the inhibition of ERK phosphorylation in xenograft models. In human tumor xenograft models, this compound induced rapid and sustained dephosphorylation of phosphorylated MEK and, consequently, inhibited phosphorylated ERK. nih.gov This inhibition of ERK phosphorylation is considered a key biomarker of MEK inhibitor activity. nih.gov For example, in pancreatic ductal adenocarcinoma (PDAC) xenografts, this compound treatment specifically decreased phosphorylated ERK levels. nih.gov Similarly, immunohistochemical analysis of thyroid cancer xenografts showed that ERK activation was significantly inhibited by this compound. spandidos-publications.com In a mouse xenograft model of malignant pleural mesothelioma, this compound blocked MEK-dependent ERK phosphorylation in a concentration-dependent manner. nih.gov Tumors from mice treated with this compound also showed the weakest staining for p-ERK. nih.gov

Impact on Ki67 Expression in Tumor Xenografts

Ki67 is a nuclear protein associated with cellular proliferation. Preclinical investigations have examined the effect of this compound on Ki67 expression in tumor xenograft models as an indicator of reduced cell division. In a BRAFV600E-containing xenograft model, dabrafenib, a BRAF inhibitor often used in combination with this compound, downregulated Ki67 expression, contributing to tumor growth inhibition. plos.org While direct data on this compound monotherapy's impact on Ki67 in BRAF V600E xenografts was less prominent in the immediate search results, studies in other xenograft models provide insight. In PDAC xenografts, effects of therapy on intratumoral proliferation corresponded with tumor growth inhibition, and this compound's effects were accompanied by changes in markers including those associated with proliferation. nih.gov Immunohistochemical staining of xenografts in an intrahepatic cholangiocarcinoma model revealed that Ki-67 staining was weakest in the this compound treatment group, indicating reduced proliferation. nih.gov Studies using different cancer cell lines in xenograft models also showed that this compound treatment led to a decrease in Ki67 expression, with a strong dose-dependent decrease observed in some sensitive cell lines. researchgate.net

Therapeutic Potential in Noonan Syndrome Preclinical Models for Cardiovascular Phenotype Amelioration

Noonan Syndrome is a developmental disorder often associated with mutations in the RAS/MAPK pathway, leading to various clinical features, including cardiovascular defects like hypertrophic cardiomyopathy. thrasherresearch.orgjacc.org Preclinical studies in mouse models of Noonan Syndrome have investigated the potential of MEK inhibitors like this compound to ameliorate these cardiovascular phenotypes. Research using a preclinical mouse model of Noonan Syndrome carrying the germline mutation RIT1M90I, which exhibit classic features including cardiovascular defects, assessed the efficacy of oral this compound. thrasherresearch.org Results indicated that daily oral administration of this compound significantly improved the cardiovascular phenotype of these mice. thrasherresearch.org A statistically significant decrease in heart weight-to-body weight ratio was observed in this compound-treated mice compared to placebo littermates. thrasherresearch.org Additionally, the studies showed a decrease in proliferating cells in the heart tissue of treated mice. thrasherresearch.org These findings suggest that MEK inhibition with this compound holds therapeutic potential for addressing the cardiovascular manifestations of Noonan Syndrome in preclinical settings. nih.govjacc.org

Efficacy in Thyroid Cancer Xenografts (BRAF- and RAS-Mutant Models)

Thyroid cancer frequently exhibits activation of the ERK pathway due to mutations in genes such as BRAF and RAS. spandidos-publications.com Preclinical studies have evaluated the efficacy of this compound in thyroid cancer xenograft models harboring these mutations. This compound has shown marked single-agent activity against both RAS- and BRAF-mutant thyroid cancer models in vitro and in vivo. spandidos-publications.com In xenografts bearing either KRASG12R or BRAFV600E mutations, this compound alone was highly effective, leading to sustained shrinkage in tumor volume compared to baseline. spandidos-publications.com Specifically, this compound was effective as a single agent against the RAS mutant CAL62 xenograft model. spandidos-publications.com These preclinical findings support the evaluation of this compound as a potential therapeutic agent in thyroid cancer with BRAF and RAS mutations. spandidos-publications.commdpi.com

Preclinical Study Findings Summary

Constitutive ERK Mutation as a Bypass Mechanism

Phosphatidylinositide 3-kinase (PI3K)/AKT Pathway Upregulation

Upregulation or activation of the PI3K/AKT pathway is a significant mechanism of both acquired and intrinsic resistance to this compound. aacrjournals.orgdovepress.com This pathway acts as a bypass mechanism, allowing cancer cells to circumvent the MEK blockade and continue to proliferate and survive. Studies have shown increased PI3K/AKT pathway activation in this compound-resistant tumors. aacrjournals.orgdovepress.com This activation can occur through various mechanisms, including genetic alterations in PI3K or AKT genes or activation by upstream signaling molecules. dovepress.com The PI3K/AKT/mTOR pathway is frequently dysregulated in cancers, contributing to uncontrolled cell growth and resistance to apoptosis. vulcanchem.com Inhibiting the PI3K/AKT pathway in combination with MEK inhibitors has been proposed as a strategy to overcome resistance. dovepress.com Research in canine mucosal melanoma, which shares parallels with human mucosal melanoma, demonstrated that resistance to this compound was reversed by inhibiting the activation of the PI3K/AKT/mTOR pathway. biorxiv.org

Role of c-Kit Activation

Activation of c-Kit, a receptor tyrosine kinase, has been implicated in mechanisms of resistance to targeted therapies, including MEK inhibitors. aacrjournals.orgmdpi.com c-Kit signaling can drive proliferation and survival through the activation of downstream pathways such as PI3K and MAPK. mdpi.com While c-KIT mutations are found in a subset of melanomas, including mucosal and acral subtypes, their role in conferring resistance to this compound specifically, independent of other resistance mechanisms, is an area of ongoing research. biorxiv.orgmdpi.com Studies have suggested increased c-Kit activation in resistant tumors. aacrjournals.orgaacrjournals.org

Genomic Adaptive Reprogramming and Enhancer Formation (e.g., BRD4 binding)

Adaptive resistance to this compound can involve significant remodeling of the genomic landscape, including the formation of new enhancers. oncoscience.usunclineberger.orgunc.edunih.gov These enhancers are DNA sequences that can increase the transcription of specific genes, allowing cancer cells to adapt and survive in the presence of the drug. unclineberger.orgunc.edu Bromodomain-containing protein 4 (BRD4), a member of the BET family of bromodomain proteins, plays a crucial role in the formation and function of these enhancers. oncoscience.usnih.govoaepublish.com BRD4 binds to acetylated histones and transcription factors, regulating transcriptional elongation. oaepublish.com Upon this compound treatment, rapid and widespread formation of enhancers with high BRD4 density has been observed, particularly near receptor tyrosine kinase (RTK) loci, contributing to their upregulation and subsequent resistance. oncoscience.usnih.govoaepublish.com Inhibiting BRD4 has shown promise in attenuating this adaptive reprogramming and restoring sensitivity to this compound in preclinical models. unclineberger.orgunc.edunih.govoaepublish.com

Epithelial-Mesenchymal Transition (EMT) and Stem-Like Phenotype Adaptation

Epithelial-Mesenchymal Transition (EMT) is a process by which epithelial cells acquire mesenchymal characteristics, often associated with increased invasiveness, migration, and resistance to therapy. Adaptation towards a stem-like phenotype has also been linked to drug resistance. Research suggests that changes in epithelial gene expression and EMT-related signatures can occur with the development of MEK inhibitor resistance. aacrjournals.org Furthermore, some studies indicate a potential shift from a stem-like subtype to an inflammatory subtype in this compound-resistant cells. nih.gov

Inflammatory Gene Expression and NFκB Activation

Acquired resistance to this compound has been associated with the upregulation of inflammatory gene expression and activation of the NFκB signaling pathway. aacrjournals.orgresearchgate.net Studies in colorectal cancer cell lines have shown that this compound resistance is linked to an enrichment of inflammatory gene signatures, with TNFα and NFκB gene sets being highly ranked. researchgate.net NFκB activation can be greater in cell lines resistant to MEK inhibition. aacrjournals.org Inflammatory cytokines or conditioned medium from macrophage cultures can induce resistance to MEK inhibition, and this is associated with increased NFκB activation. aacrjournals.org The bromodomain inhibitor JQ1 has been shown to suppress inflammatory gene expression and NFκB activation, and in combination with MEK inhibitors, it can overcome resistance. aacrjournals.orgnih.gov

Combination Therapy Approaches

Combining this compound with other targeted agents or therapies is a widely explored strategy to overcome or delay resistance. The rationale is to simultaneously block multiple pathways that contribute to tumor growth and survival or to target the specific resistance mechanisms that emerge.

A prominent example is the combination of this compound with a BRAF inhibitor, such as dabrafenib. This combination has shown significantly improved response rates and progression-free survival compared to BRAF inhibition alone in patients with BRAF V600-mutated melanoma and other solid tumors. ascopubs.orgoncotarget.comfda.govcancer.govnih.govjhoponline.com The combination mitigates a key resistance pathway that involves MEK activation compensating for BRAF inhibition. cancer.govbmj.com

Combination therapies can target various resistance mechanisms:

Targeting the PI3K/AKT pathway: Combining MEK inhibitors with inhibitors of the PI3K/AKT pathway may overcome resistance driven by the activation of this bypass route. aacrjournals.orgnih.gov For instance, studies suggest that combining this compound with a PI3K inhibitor like GSK2126458 can be effective in colorectal cancer cells resistant to this compound. nih.gov

Targeting RTKs: Inhibiting activated RTKs that contribute to resistance, such as MET or EGFR, in combination with this compound, can be a strategy. ascopubs.orgamegroups.orgmdpi.comfrontiersin.org Adding EGFR monoclonal antibodies to BRAF/MEK combinations has shown benefit in colorectal cancer with intrinsic resistance. ascopubs.org Triple-targeted therapy involving EGFR, BRAF, and MEK inhibitors is being investigated for specific resistance scenarios in NSCLC. amegroups.org

Targeting other kinases: Combining this compound with inhibitors of other kinases involved in resistance, such as ERK or BRD4, is under investigation. mdpi.comunclineberger.org Preclinical studies have shown that pairing this compound with an investigational anti-BRD4 drug can prevent the onset of resistance in triple-negative breast cancer models by inhibiting adaptive reprogramming. unclineberger.org

Targeting RAF dimers: Type II RAF inhibitors, which are effective against RAF dimers, in combination with this compound, can overcome resistance to type I RAF and MEK inhibitors, particularly in anaplastic thyroid cancer. medrxiv.org

Data from clinical trials highlight the benefits of combination therapy. The combination of dabrafenib and this compound has demonstrated consistent response rates in various tumor types harboring the BRAF V600E mutation. ascopubs.org

Intermittent Dosing and Drug Rechallenge Strategies

Intermittent dosing and drug rechallenge are alternative strategies explored to manage or overcome this compound resistance, particularly acquired resistance. The concept behind these approaches is based on the observation that some resistance mechanisms may be reversible or that temporary drug withdrawal could re-sensitize tumor cells to treatment. mdpi.comresearchgate.netnih.govfrontiersin.org

Preclinical research in animal models initially suggested that intermittent dosing of BRAF and MEK inhibitors might delay acquired resistance by altering the selective pressure on tumor cells. onclive.comoncology-central.comecancer.org This hypothesis proposed that intermittent exposure could select for tumor cells that remain sensitive to the treatment for a longer duration. onclive.com

However, clinical trial data have provided contrasting results. The phase 2 SWOG S1320 trial investigated intermittent versus continuous dosing of dabrafenib and this compound in patients with advanced BRAF V600-mutant melanoma. onclive.comoncology-central.comonclive.com The study found that continuous dosing resulted in superior progression-free survival compared to intermittent dosing. onclive.comecancer.orgonclive.com This outcome was contrary to the preclinical findings. onclive.comonclive.com Possible explanations for this discrepancy include differences in drug metabolism and resistance mechanisms between humans and mice, and the potential for non-MAPK resistance pathways to be more dominant in human patients. frontiersin.orgonclive.com

Despite the findings from the SWOG S1320 trial regarding intermittent dosing to delay resistance, drug rechallenge after a period of drug holiday following acquired resistance remains a potential therapeutic option in the salvage setting for some patients. mdpi.comfrontiersin.org It has been demonstrated in preclinical models that certain resistance mechanisms are reversible, and after a "drug holiday," some patients may regain sensitivity. frontiersin.org Studies in this compound-resistant melanoma cell lines have shown that alternating periods of drug withdrawal and rechallenge can be highly responsive, particularly in cells displaying a differentiation phenotype. mdpi.comnih.govdntb.gov.ua This suggests that melanoma cell plasticity plays a role, where resistant cells adapt to altered conditions but can be influenced by drug re-exposure. researchgate.netnih.gov

In clinical practice, rechallenge with dabrafenib and this compound has been explored in patients with metastatic melanoma who progressed after initial targeted therapy and subsequent immunotherapy. frontiersin.org While the duration of the drug holiday did not appear to be associated with the incidence of response in one analysis, the strategy has shown some clinical activity. frontiersin.org

Dabrafenib (BRAF Inhibitor) and this compound Combination

The combination of dabrafenib, a BRAF inhibitor, and this compound has become a standard of care for patients with unresectable or metastatic melanoma harboring BRAF V600E or V600K mutations. pensoft.netbecarispublishing.comascopubs.org This combination targets two different kinases within the same signaling pathway. pensoft.net

Results from the COMBI-v trial showed a median progression-free survival of 12.6 months for the combination group compared with 7.3 months for vemurafenib alone. nice.org.uk The objective response rate was 64% for combination therapy and 51% for vemurafenib monotherapy in this trial. pensoft.net A meta-analysis indicated that dabrafenib + this compound significantly prolongs survival outcomes compared with monotherapies. becarispublishing.com

The combination of BRAF and MEK inhibitors has been shown to delay the emergence of resistance compared with BRAF inhibitor monotherapy. researchgate.netascopubs.orgaacrjournals.org This is attributed to the dual blockade of the MAPK pathway, which can prevent or delay resistance mechanisms that arise through pathway reactivation. becarispublishing.com

Here is a data table summarizing key efficacy outcomes from clinical trials comparing dabrafenib and this compound combination therapy to monotherapy in BRAF V600-mutated melanoma:

While combination therapy can lead to higher rates of adverse events, the toxicity profile of the dabrafenib and this compound combination has been reported as manageable, and in some cases, the combination may even prevent complications associated with BRAF inhibitor monotherapy. ascopubs.orgascopubs.org For example, the combination regimen using full doses of both drugs generated fewer adverse skin events than BRAF inhibitor monotherapy. dovepress.com The lower incidence of squamoproliferative lesions during combined inhibition is possibly related to blocking of paradoxical MAPK signaling downstream of CRAF by MEK inhibition. dovepress.com

Extensive clinical experience with the combination in metastatic melanoma has provided a wealth of strategies to identify and manage associated adverse events. nih.gov Understanding the adverse event profile and possible strategies to mitigate these toxicities is important. ascopubs.orgascopubs.org

Improved Efficacy and Delay of Resistance

Combination with Immunotherapies (e.g., Anti-PD-1, Anti-CTLA-4 Antibodies)

Combining MAPK pathway inhibitors, such as dabrafenib and this compound, with immunomodulatory antibodies targeting CTLA-4 or PD-L1/PD-1 is an area of significant clinical interest. aacrjournals.org Preclinical studies have explored the potential synergistic effects of these combinations. oncotarget.comnih.gov

In preclinical models, the addition of an anti-PD-1 antibody to combined dabrafenib and this compound was associated with superior outcomes compared with relevant controls. targetedonc.com Preclinical evidence has also shown that combined therapy of dabrafenib, this compound, and anti-PD-1 provided superior antitumor activity against established BRAF V600E mutant murine melanoma compared with anti-PD-1 plus either therapy alone, or isotype control with both dabrafenib and this compound. nih.gov In vitro studies indicated that the combination of dabrafenib, this compound, and anti-PD-1 increases CD8+ tumor infiltrating lymphocytes (TILs), as well as CD4+ T cells and tumor-associated macrophages (TAMs). nih.gov

Clinical trials are evaluating the efficacy and tolerability of combining targeted therapy (dabrafenib and this compound) with immunotherapy (e.g., pembrolizumab). aacrjournals.org While preclinical data support the synergistic effect of both modalities, data confirming the activity and tolerability of these combinations are still being gathered in the clinical setting. oncotarget.com

Combination with PI3K/AKT/mTOR Inhibitors (e.g., Everolimus, GSK2141795)

The combination of MEK inhibitors like this compound with inhibitors of the PI3K/AKT/mTOR pathway has been investigated as a strategy to overcome resistance mechanisms and enhance therapeutic efficacy in various cancer types. Preclinical studies have shown that therapies are more effective when drugs targeting the PI3K-Akt-mTOR pathway are combined with inhibitors of other pathways, such as RAS-MEK-ERK. mdpi.com

A phase I trial investigated the safety, tolerability, and recommended phase 2 dose for the pan-PI3K/mTOR inhibitor, GSK2126458, and this compound combination when administered to patients with advanced solid tumors. nih.gov While mutations in RAS/RAF/PI3K were detected in a significant percentage of patients, minimal responses were observed, potentially due to overlapping toxicities that limited sufficient dose exposure. nih.gov

The combination of this compound and the PI3K/mTOR dual inhibitor GSK2126458 also enhanced cell growth inhibition in B-Raf inhibitor-resistant BRAF mutant melanoma cell lines. oncotarget.com

A phase I trial is studying the side effects and best dose of neratinib in combination with everolimus, palbociclib, or this compound in participants with solid tumors with specific mutations (EGFR, HER2, HER3/4, or KRAS) that are refractory and metastatic. mdanderson.org Giving neratinib with everolimus, palbociclib, or this compound may work better than neratinib alone in treating these participants. mdanderson.org

A phase I trial evaluated the combination of this compound and everolimus in pediatric and young adult patients with recurrent low-grade and high-grade gliomas. cancer.govucsf.edu This study aims to determine the recommended phase 2 dose of this combination. ucsf.edu

A single-arm, single-stage phase II trial is evaluating the combination of this compound (GSK1120212) and GSK2141795, an AKT inhibitor, in patients with recurrent or persistent cervical cancer. dana-farber.org The study aims to determine if this combination is useful in treating this type of cancer and if tumors with a particular genetic makeup show a better response. dana-farber.org Another phase II trial studied how well this compound and Akt inhibitor GSK2141795 work in treating patients with metastatic triple-negative breast cancer. mycancergenome.org This trial included a design where patients initially received this compound monotherapy and, upon disease progression, continued with this compound in combination with GSK2141795. mycancergenome.org

In uveal melanoma, a randomized trial compared this compound alone versus this compound combined with the Akt inhibitor GSK2141795, revealing no difference in median progression-free survival and only one partial response in each group. researchgate.net

Preclinical studies in meningioma have shown that MEK inhibition leads to PI3K/AKT activation, and co-targeting both pathways with a combination of the PI3K inhibitor alpelisib and this compound provided an additive effect on inhibiting cell viability. mdpi.com

A phase II clinical trial is investigating the clinical effect of this compound combined with everolimus and lenvatinib in the treatment of recurrent/refractory advanced solid tumors. careboxhealth.comclinicaltrial.beveeva.com

Combination with Pazopanib in Thyroid Cancer

Preclinical findings support the evaluation of this compound, alone or in combination with pazopanib or other kinase inhibitors, in thyroid cancer clinical trials. spandidos-publications.comresearchgate.net Studies have shown that the combination of this compound and pazopanib resulted in synergistic inhibition of tumor growth in thyroid cancer cell lines and xenograft models. spandidos-publications.comresearchgate.net

A phase I study evaluated the safety and efficacy of pazopanib and this compound in advanced solid tumors with an expansion cohort in differentiated thyroid cancer (DTC). nih.govgisttrials.org The combination showed clinical activity in DTC but did not achieve the prespecified response rate target. nih.gov In this study, objective response in the DTC cohort was 33%, and median progression-free survival was 10.7 months. nih.gov NRAS mutation was associated with response in this cohort. nih.gov

Table 1: Pazopanib and this compound Combination in Differentiated Thyroid Cancer (Phase I Expansion Cohort)

Combination with Naporafenib in NRAS-Mutant Melanoma

The combination of naporafenib and this compound is being investigated for the treatment of unresectable or metastatic NRAS-mutant melanoma. A global, randomized, open-label Phase III study, SEACRAFT-2, is assessing the efficacy and safety of naporafenib administered with this compound compared to physician's choice of therapy (dacarbazine, temozolomide, or this compound monotherapy) in patients who have progressed on or are intolerant to a PD-1/PD-L1–based regimen. clinicaltrial.bemskcc.org

Combination with GNS561 in KRAS-Mutated Cholangiocarcinoma

A Phase 1b/2a study is combining GNS561 with this compound for advanced cholangiocarcinoma with a KRAS mutation. cancer.govclinicaltrials.eufroedtert.com This study aims to assess the safety and efficacy of this combination. froedtert.com Data from the ongoing Phase 1b portion is expected by year-end 2025 to support dose selection for Phase 2.

Combination with Azacitidine in Juvenile Myelomonocytic Leukemia

The combination of this compound and azacitidine is being investigated for the treatment of juvenile myelomonocytic leukemia (JMML). Preclinical studies have shown potential synergy between these two agents. ashpublications.org Researchers have found that the hypomethylating agent azacitidine plus the MEK inhibitor this compound may be a promising new combination to treat patients with JMML, according to a preclinical study. ascopost.com This combination may be capable of reducing some of the cancerous features of the disease by decreasing the number of cancerous blood stem cells and reducing the activity of the RAS/MAPK pathway. ascopost.com

A risk-stratified, non-randomized phase I/II clinical trial (T2020-004) is designed to examine the safety and efficacy of this compound in combination with other agents for children and young adults with newly diagnosed JMML. ashpublications.orgusc.educancer.gov In this trial, patients with lower-risk JMML will be treated with azacitidine in combination with this compound. ashpublications.orgusc.educancer.gov Patients with high-risk JMML will receive azacitidine and this compound in combination with chemotherapy. usc.educancer.gov This trial represents the first risk-stratified treatment strategy for patients with JMML and the first to use this combination of azacitidine and this compound. ashpublications.org

Combination with Anti-BRD4 Drugs for Resistance Prevention

Research has explored combining this compound with anti-BRD4 drugs to overcome or prevent resistance to MEK inhibition. In triple-negative breast cancer cells treated with this compound, resistance involved the formation of new enhancers bound by molecules like BRD4, which help turn on genes. unclineberger.orgunc.edu Pairing an investigational anti-BRD4 drug with this compound helped to stop tumor growth in experiments in cells and mouse models. unclineberger.orgunc.edu This combination was able to inhibit the reprogramming of tumor cells, potentially preventing or reversing the development of resistance to this compound. unclineberger.orgunc.edu

Studies in NF1-deficient ovarian cancer cell lines showed that MEK inhibitors were not durably effective due to kinome reprogramming. nih.gov MEK inhibitor-mediated destabilization of FOSL1 led to induced expression of receptor tyrosine kinases (RTKs) and their downstream signaling, contributing to overcoming MEK inhibitor therapy. nih.gov Inhibition of BET proteins using BET bromodomain inhibitors (BETi) blocked MEK inhibitor-induced RTK reprogramming, indicating that BRD2 and BRD4 are potential therapeutic targets in combination with MEK inhibitors to block resistance due to kinome reprogramming. nih.gov

Metastatic Melanoma (BRAF V600E/K-Mutated, NRAS-Mutant, BRAF/NRAS Wild-Type)

This compound has played a significant role in the treatment of metastatic melanoma, both as a monotherapy and, notably, in combination with the BRAF inhibitor dabrafenib. Aberrant MAPK pathway signaling is a hallmark of melanoma. nih.gov

In patients with BRAF V600E or BRAF V600K mutated unresectable or metastatic melanoma, the combination of dabrafenib and this compound has shown significant superiority in terms of objective response rate (ORR) and progression-free survival (PFS) compared to dabrafenib monotherapy. frontiersin.org A phase III study (METRIC) evaluating this compound monotherapy in patients with metastatic BRAF V600E or BRAF V600K mutations demonstrated improved response rates and PFS compared to chemotherapy. This compound achieved a 22% response rate and a median PFS of 4.8 months, versus 8% and 1.5 months for chemotherapy, respectively. nih.govmdpi.com Updated analysis of the METRIC trial showed a median PFS of 4.9 months and a median OS of 15.6 months for this compound monotherapy, compared to 1.5 months PFS and 11.3 months OS in the chemotherapy group. mdpi.com

For NRAS-mutant melanoma, MEK inhibition with this compound may have a role. In a phase I clinical trial, this compound was associated with stable disease in 2 out of 7 treated patients. nih.gov A phase I study combining this compound with paclitaxel in BRAF wild-type melanoma, which included patients with NRAS-mutant melanoma, demonstrated a 40% partial response rate, with 4 out of 6 patients with NRAS-mutant melanoma experiencing a response. nih.gov

In BRAF wild-type advanced melanoma that has progressed after immunotherapy, a retrospective study of this compound treatment in 22 patients (20 with NRAS mutations, 1 with NF1, 1 with GNA11) showed disease control in 36% of patients (6 stable disease, 2 partial responses). The median PFS was 2 months, and median OS was 6.5 months. researchgate.net Preclinical evidence suggests activity of this compound in BRAF/NRAS wild-type melanoma cell lines, including those with loss of NF1. nih.gov An early phase I study of this compound monotherapy resulted in partial responses (10%) in wild-type melanoma patients. nih.gov A phase II trial investigating this compound with or without low-dose dabrafenib in advanced, previously treated BRAF V600/NRAS Q61 wild-type melanoma showed a confirmed ORR of 29.2% with the combination. The median PFS was 13.3 weeks, and median OS was 54.3 weeks. nih.govresearchgate.net

Table 1: Summary of this compound Efficacy in Metastatic Melanoma

Non-Small Cell Lung Cancer (BRAF V600E-Mutated)

The combination of dabrafenib and this compound has demonstrated efficacy in the treatment of BRAF V600E-mutated non-small cell lung cancer (NSCLC). theoncologynurse.comnih.gov A multicenter, open-label phase 2 study (BRF113928) evaluated the combination in both pretreated and treatment-naïve patients with metastatic BRAF V600E-mutant NSCLC. theoncologynurse.com

A single-arm, open-label, multicentre phase II study (NCT04452877) in Chinese patients with BRAF V600E mutation-positive metastatic NSCLC treated with dabrafenib plus this compound reported an ORR of 75%. amegroups.org At the data cut-off, the median duration of response, PFS, and OS were not reached. amegroups.org At 4 months, 90.0% of patients showed a response, and 91.7% achieved PFS. amegroups.org

Table 2: Summary of Dabrafenib + this compound Efficacy in BRAF V600E-Mutated NSCLC

Thyroid Cancer (Anaplastic, BRAF-Mutated)

The combination of dabrafenib plus this compound has received approval in several countries for the treatment of BRAF V600E-mutant anaplastic thyroid cancer (ATC). uax.com This was based on data from the phase II Rare Oncology Agnostic Research (ROAR) basket study. uax.comnih.gov

An updated analysis of the ROAR ATC cohort, including 36 patients with unresectable or metastatic BRAF V600E-mutant ATC, demonstrated meaningful clinical activity. uax.comnih.gov The investigator-assessed ORR was 56%, including three complete responses. uax.comnih.gov The 12-month duration of response rate was 50%. uax.comnih.gov Median PFS was 6.7 months, and median OS was 14.5 months. uax.comnih.gov The 12-month PFS and OS rates were 43.2% and 51.7%, respectively, and the 24-month OS rate was 31.5%. uax.comnih.gov These survival rates are notable given the historically poor median OS of less than 6 months in patients with ATC. uax.comnih.gov

A retrospective study evaluating dabrafenib and this compound in 27 patients with metastatic BRAF V600E-mutated papillary thyroid cancer (PTC), including eight with poorly differentiated or anaplastic transformation, reported an ORR of 73.1% and a disease control rate (DCR) of 92.3%. e-crt.org Median PFS and OS were both 21.7 months in this cohort. e-crt.org

Table 3: Summary of Dabrafenib + this compound Efficacy in BRAF V600E-Mutated Anaplastic Thyroid Cancer

Colorectal Cancer (BRAF-Mutant, KRAS-Mutated)

The RAS/RAF/MEK/ERK signaling pathway is critical in colorectal cancers, and KRAS, NRAS, and BRAF mutations are common. aacrjournals.org Colorectal cancers harboring KRAS, NRAS, or BRAF-activating mutations are known to have worse prognoses. aacrjournals.org

Single-agent MEK inhibition has shown limited activity in BRAF-mutant metastatic colorectal cancer (mCRC). An early phase I study of this compound in patients with treatment-refractory KRAS- or BRAF-mutant advanced CRC did not identify an objective response in 28 patients. amegroups.org

Combination strategies targeting the MAPK pathway have been explored in BRAF-mutant CRC. A phase I/II trial of dabrafenib and this compound in 36 patients with BRAF-mutated CRC found that 1 patient achieved a complete response, and 3 had an unconfirmed partial response. onclive.com Another study of dabrafenib and this compound in 43 patients with BRAF-mutant CRCs reported disease control in 27 patients (22 stable disease, 4 partial response, 1 complete response). dovepress.com

Preclinical studies have investigated combining this compound with other agents in KRAS-mutated CRC. High-throughput screening identified paclitaxel as synergistic with this compound in KRAS-mutated CRC spheroids and cell lines, enhancing cell death and inhibiting tumor growth in patient-derived xenografts. nih.gov These preclinical findings support further clinical investigation of this combination in KRAS-mutated mCRC. nih.gov

Multiple Myeloma

Activating mutations of the MAPK pathway are reported in over half of myeloma tumors. researchgate.net While experience with MEK inhibitors in solid tumors suggests that tumors harboring BRAF or RAS mutations are more likely to respond, response rates and duration of responses can be limited. researchgate.net

Early anecdotal activity with the combination of dabrafenib and this compound has been noted in multiple myeloma. frontiersin.org A retrospective analysis identified 58 this compound-treated relapsed/refractory multiple myeloma (RRMM) cases, of which 51 harbored KRAS, NRAS, or BRAF mutations. frontiersin.org Single-agent this compound showed early success in isolated individuals, including one KRAS-mutated patient with multiply relapsed myeloma who achieved an impressive response. frontiersin.org

Oral Cavity Squamous Cell Carcinoma (OCSCC)

Ras/MEK/ERK pathway activation is common in oral cavity squamous cell carcinoma (OCSCC). aacrjournals.orgnih.govaacrjournals.org A phase II neoadjuvant window-of-opportunity clinical trial evaluated this compound in patients with stage II–IV OCSCC prior to surgery. aacrjournals.orgnih.govaacrjournals.orgresearchgate.net

In this study, this compound administration led to a significant reduction in Ras/MEK/ERK pathway activation and a decrease in CD44 expression. aacrjournals.orgnih.gov A clinical tumor response, based on modified World Health Organization criteria, was observed in 11 out of 17 (65%) evaluable patients, with a median decrease of 46%. aacrjournals.orgnih.govresearchgate.net A partial metabolic response (≥25% reduction in SUVmax) was observed in 6 out of 13 (46%) evaluable patients, with a median decrease of 25%. aacrjournals.orgnih.govresearchgate.net Clinical-to-pathologic tumor downstaging occurred in 9 out of 17 (53%) evaluable patients. aacrjournals.orgnih.govresearchgate.net These findings suggest that this compound is a promising therapeutic option for OCSCC patients. nih.govbohrium.com

Table 4: Summary of this compound Efficacy in Neoadjuvant OCSCC

High-Grade Gliomas (Pediatric and Young Adult)

Gliomas are the most common primary brain and CNS tumors in children and adolescents, with pediatric high-grade gliomas (pHGGs) accounting for a significant proportion. ascopubs.org The BRAF V600 mutation is detected in 5%-10% of pHGGs. ascopubs.orgesmo.org

The combination of dabrafenib plus this compound has shown promising results in pediatric and young adult patients with relapsed/refractory BRAF V600-mutated high-grade gliomas. ascopubs.orgesmo.orgnih.gov A phase II study evaluated this combination in 41 pediatric patients with previously treated BRAF V600-mutant HGG. ascopubs.orgesmo.org

The independently assessed ORR was 56%. ascopubs.orgesmo.org The median duration of response (DoR) was 22.2 months. ascopubs.orgesmo.org Median OS was 32.8 months. ascopubs.org These results compare favorably with historical data from molecularly unselected cohorts of relapsed/refractory pHGG. ascopubs.orgesmo.org Younger age, BRAF V600 mutation, and longer therapy periods were associated with better radiological outcomes in pediatric patients. nih.gov

A systematic review and meta-analysis comparing outcomes of dabrafenib plus this compound in pediatric and adult gliomas (including low-grade gliomas) with BRAF V600 mutations found a higher, though not statistically significant, ORR (53% vs. 39%) and clinical benefit rate (87% vs. 73%) in pediatric patients compared to adults. nih.gov

Table 5: Summary of Dabrafenib + this compound Efficacy in Relapsed/Refractory BRAF V600-Mutated Pediatric High-Grade Glioma

Cholangiocarcinoma

Cholangiocarcinoma (CCA), a cancer of the bile ducts, is often diagnosed at advanced stages with limited treatment options. mdanderson.orgbjmo.be Approximately 5% of biliary tract tumors harbor BRAF V600E mutations, which activate the MAPK pathway. bjmo.bemdpi.com The combination of dabrafenib (a BRAF inhibitor) and this compound has shown promise in patients with BRAF V600E-mutated CCA. mdanderson.orgbjmo.betargetedonc.com

Another phase IIa study investigated this compound alone in 20 Japanese patients with advanced biliary tract cancers refractory to gemcitabine-based therapy. withpower.comnih.gov The 12-week non-progression rate was 10%, which did not meet the target threshold. withpower.comnih.gov The median PFS was 10.6 weeks. nih.gov

Ongoing research continues to explore this compound in CCA, including in combination with other agents. A Phase 1b/2a study (NCT04296945) is evaluating GNS561 in combination with this compound in advanced KRAS-mutated CCA. uvahealth.com Preclinical studies also suggest that this compound may improve the immunogenicity of tumor cells, potentially enhancing the efficacy of combination therapy with anti-PD-1 antibodies in intrahepatic CCA models. nih.gov

Juvenile Myelomonocytic Leukemia

Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive childhood myeloproliferative disorder characterized by aberrant signaling through the Ras pathway, often due to mutations in genes such as PTPN11, KRAS, NRAS, and NF1. ashpublications.orgaacrjournals.orgaacr.org Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment, but outcomes are poor for patients with relapsed or refractory disease. ashpublications.orgaacrjournals.org

This compound, as a MEK inhibitor targeting the Ras/MAPK pathway, has been investigated in pediatric patients with JMML. ashpublications.orgaacrjournals.orgaacr.org A phase II clinical trial (ADVL1521, NCT03190915) conducted by the Children's Oncology Group evaluated this compound monotherapy in children with relapsed or refractory JMML. ashpublications.orgaacrjournals.orgaacr.orgnih.gov Ten patients were enrolled, and the objective response rate was 50%, including two complete responses and three partial responses. aacrjournals.orgaacr.orgnih.gov Seven of the 10 patients were alive after a median follow-up of two years. aacrjournals.orgaacr.orgnih.gov Four patients with refractory disease proceeded to HSCT after receiving this compound. aacrjournals.orgnih.gov Three patients completed the maximum 12 cycles and continued on off-protocol this compound without HSCT. aacrjournals.orgnih.gov

A phase 1/2 non-randomized study (T2020-004, NCT05849662) is evaluating this compound in combination with azacitidine in newly diagnosed lower-risk JMML patients and in combination with azacitidine, fludarabine, and cytarabine in high-risk patients. ashpublications.orgcincinnatichildrens.orgcancer.gov Preclinical studies using JMML patient-derived xenograft mouse models have also demonstrated that this compound monotherapy significantly prolongs survival by inhibiting the RAS pathway. tandfonline.comnih.gov

Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks expression of estrogen receptor, progesterone receptor, and HER2, limiting targeted therapy options. researchgate.netega-archive.orgaacrjournals.org Preclinical data suggest that activation of the RAS/MEK/ERK pathway may contribute to chemotherapy resistance in TNBC. aacrjournals.org

Research has explored the potential of targeting the MEK pathway with this compound in TNBC. A phase II study (OSU 13317) investigated this compound alone and in combination with the AKT inhibitor uprosertib in patients with metastatic TNBC previously treated with chemotherapy. aacrjournals.orgoncodaily.com In the this compound alone arm, 2 out of 37 enrolled patients had a partial response, and 6 had stable disease. aacrjournals.org In the combination arm (19 evaluable patients), 3 patients had a partial response and 3 had stable disease. aacrjournals.org While this compound monotherapy showed limited efficacy, the combination with uprosertib was associated with a numerically greater objective response rate. oncodaily.com

Studies have also investigated mechanisms of resistance to this compound in TNBC. Researchers have found that TNBC cells can develop resistance by altering their genetic landscape and forming new enhancers that turn on alternative protein pathways. unclineberger.org Combining this compound with an anti-BRD4 drug in laboratory models helped to inhibit this reprogramming and prevent the onset of resistance. unclineberger.org Preclinical studies have also shown that ONC201 and this compound synergistically inhibit the growth of TNBC cells. researchgate.net

Treatment of Noonan Syndrome-Associated Cardiovascular Manifestations

Noonan syndrome (NS) is a genetic disorder caused by mutations in genes involved in the Ras/MAPK signaling pathway, including PTPN11, KRAS, SOS1, and RAF1. frontiersin.orgradboudumc.nlnih.gov These mutations lead to an overactivation of the pathway and can result in various clinical features, including severe cardiovascular anomalies such as hypertrophic cardiomyopathy (HCM) and pulmonary valve stenosis (PVS). frontiersin.orgradboudumc.nlnih.govmdpi.com

Given the role of the hyperactive Ras/MAPK pathway in the pathogenesis of NS-associated cardiovascular manifestations, MEK inhibitors like this compound have been explored as a potential targeted therapy. frontiersin.orgradboudumc.nlnih.govjacc.org Retrospective studies and case reports have described the use of this compound in infants and children with severe NS-associated cardiac and lymphatic issues. frontiersin.orgradboudumc.nlnih.govchusj.orgnih.gov

A retrospective study analyzing the clinical records of 61 NS patients with thickening of the heart muscle showed that children who received compassionate use of this compound in addition to standard treatment had a lower risk of death, heart transplantation, or other major heart surgeries compared to those receiving standard treatment alone. radboudumc.nlchusj.org Over a three-year period, the probability of these events was 20% for children treated with this compound, compared to 80% for those on standard treatment. chusj.org The study also indicated that the cardiac status of patients treated with this compound improved. radboudumc.nl

Case reports have also documented positive responses to this compound in severe cases. For instance, a preterm infant with congenital pulmonary lymphangiectasis and chylothorax refractory to conventional management showed resolution of chylothorax and gradual pulmonary function improvement after a five-week course of this compound. frontiersin.orgnih.govnih.gov this compound treatment has also been associated with regression of left ventricular hypertrophy and improved cardiac function in patients with NS-related HCM. jacc.orgahajournals.org

While formal clinical trials of this compound specifically for neonatal/pediatric NS-associated cardiovascular manifestations are limited, the available evidence from retrospective studies and case series suggests that this compound is a promising drug in this setting. frontiersin.orgnih.govnih.gov Further clinical trials are considered warranted to establish standardized protocols and confirm efficacy and safety. frontiersin.orgnih.govnih.govresearchgate.net Preclinical studies in mouse models of NS have also demonstrated that this compound can improve the cardiovascular phenotype, including a decrease in heart weight-to-body weight ratio and reduced proliferating cells in the heart. thrasherresearch.org

BRAF V600E/K Mutations

Mutations in the BRAF gene, particularly the V600E and V600K alterations, are well-established predictive biomarkers for response to this compound, especially in melanoma. nih.govmycancergenome.orgnih.govmdpi.com These mutations lead to constitutive activation of BRAF, a kinase upstream of MEK in the MAPK pathway. aacrjournals.org this compound, by inhibiting MEK, blocks the downstream signaling driven by mutated BRAF. mdpi.com

NRAS Mutations

NRAS mutations are also being investigated as predictive biomarkers for this compound sensitivity. NRAS mutations are found in a significant subset of melanomas (15%-20%) and can also occur in other cancers like NSCLC (0.5-1%) and pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) (up to 44.2% of cases with RAS pathway mutations). nih.govsmw.chnih.govaacrjournals.org Preclinical data suggest that cell lines with NRAS mutations are sensitive to MEK inhibitors like this compound. smw.chaacrjournals.org

Clinical studies have explored the efficacy of MEK inhibitors in NRAS mutant melanoma. In a phase II study of binimetinib (another MEK inhibitor), a 20% partial response rate was observed in patients with NRAS mutant melanoma. nih.gov A phase I study combining this compound with paclitaxel in BRAF wild-type melanoma, which included NRAS mutant cases, showed a 40% partial response rate, with 4 out of 6 NRAS-mutant patients experiencing a response. nih.gov While NRAS mutations show promise as a predictive marker, further clinical validation is needed, particularly for this compound monotherapy. smw.ch

Dynamic Molecular Markers of Pathway Inhibition (e.g., p-ERK1/2, p27, cyclin D1)

Dynamic biomarkers, assessed after the initiation of treatment, can indicate whether this compound is effectively inhibiting the MAPK pathway. Phosphorylated ERK1/2 (p-ERK1/2) is a direct downstream target of MEK, and its reduction upon this compound treatment indicates effective pathway inhibition. nih.govaacrjournals.org Studies have shown that this compound induces rapid and sustained dephosphorylation of p-ERK1/2 in sensitive cell lines and tumor models. nih.gov In a clinical trial in oral cavity squamous cell carcinoma (OCSCC), this compound treatment resulted in a significant reduction in p-ERK1/2 expression in a subset of patients. aacrjournals.org

Changes in cell cycle regulatory proteins like p27 and cyclin D1 are also observed following MEK inhibition. This compound has been shown to induce p27 accumulation and downregulate cyclin D1, suggesting cell cycle arrest. nih.govnih.govnih.govresearchgate.net These changes reflect the impact of MAPK pathway inhibition on cell cycle progression. researchgate.net

Markers of Cellular Outcomes (e.g., Cleaved PARP, phospho-4E-BP1, phospho-AKT)

Beyond direct pathway inhibition, markers reflecting cellular outcomes like apoptosis or altered protein synthesis can predict response. Cleaved PARP is a marker of apoptosis. nih.govoup.comnih.govaacrjournals.org Studies in NSCLC cell lines showed that PARP cleavage occurred in a subset of lines sensitive to this compound, suggesting that apoptosis is a mechanism of response in some contexts. nih.gov

Phosphorylation of 4E-BP1 (phospho-4E-BP1) is involved in regulating protein synthesis, and its modulation can reflect the impact of MEK inhibition on this process. nih.govoup.comresearchgate.netresearchgate.net Increased phospho-4E-BP1 has been observed in some this compound-treated cells, suggesting varied cellular outcomes, including potentially senescence or autophagy. nih.govresearchgate.netresearchgate.net

Phosphorylated AKT (phospho-AKT) is a marker of the PI3K/AKT/mTOR pathway, which can be activated in response to MEK inhibition and contribute to resistance. oup.comresearchgate.netmdc-berlin.de While complex, the modulation of phospho-AKT levels following this compound treatment may provide insights into cellular responses and potential compensatory pathway activation. researchgate.net

MAPK Pathway-Activating Alterations

Beyond BRAF and NRAS mutations, other alterations that activate the MAPK pathway can potentially serve as predictive biomarkers for MEK inhibitor sensitivity. These include mutations in KRAS, NF1, and MAP2K1 (which encodes MEK1). smw.chnih.govaacrjournals.orgamegroups.orgmdpi.comascopubs.org Patients with activating mutations in canonical MAPK pathway components have been reported to respond more frequently to MEK inhibitors compared to those without such mutations. amegroups.org

Research in low-grade serous ovarian carcinoma (LGSOC) with KRAS, BRAF, or NRAS mutations showed markedly higher PFS and ORR with this compound compared to wild-type cases. amegroups.org Functional assays measuring the level of MAPK pathway activation induced by different RAS mutations have also shown correlation between higher activity scores and longer PFS after MEK inhibitor treatment. ascopubs.org