MEK Inhibitor Research Articles (Page 1)

NF2-related schwannomatosis (NF2-SWN) is a genetic predisposition to develop multiple schwannomas that cause serious neurological disabilities for which there are no approved drug therapies. We previously reported that the MEK inhibitor trametinib slowed schwannoma growth in two mouse models, however, ERK reactivation was observed. Pathway analysis of the proteome of trametinib-treated mouse schwannoma model cells predicted activation of BRD4. To elucidate the adaptive mechanisms contributing to cell survival, we studied the trametinib response in novel immortalized and non-immortalized human schwannoma model cells (MD-HSCs). MD-HSCs exposed to trametinib avoid cell death by upregulating expression of ECM and cell adhesion proteins resulting in an increase in cell size, stress fiber formation, and a switch from c-Jun to Krox20/Egr2 nuclear expression. We demonstrate that BET proteins mediate the survival response to trametinib in MD-HSCs. Preventing this epigenetic adaptation to trametinib with BET inhibitors induces schwannoma cell death. However, this response is not observed when BET inhibitors are combined with brigatinib, a multi-kinase inhibitor in clinical use. These findings highlight the complex cellular adaptations in schwannomas and suggest that targeting BET alongside MEK inhibition prevents resistance mechanisms and promotes cell death.

We found that, in guinea pig airway smooth muscle, the pharmacological inhibition of RTKs significantly decreased the contraction induced by 20 mM KCl. We observed that MEK pharmacological inhibitors diminished the contraction induced by 20 mM KCl, but not that induced by 60 mM. On the other hand, ERK inhibitors also altered the contraction generated by 20 mM KCl. When a ROCK inhibitor was tested, we found that it significantly inhibited the KCl-induced contraction. These results were complemented with Western blot experiments, and a decrease in ERK phosphorylation was noticed when the RTKs were inhibited. When MEK and ERK inhibitors were used, we also observed a decrease in ERK phosphorylation. In the case of MYPT1, its phosphorylation decreased when RTK, MEK, and ROCK inhibitors were used. In conclusion, we found that, in guinea pig airway smooth muscle, the contraction induced by 20 mM KCl includes the activation of RTKs and, in turn, MEK-ERK and ROCK.

HPV-negative (-) head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous cancer characterized by high mutational burden, an immunosuppressive microenvironment, and poor response to standard therapies. These features highlight the urgent need for novel and more effective treatment strategies. Drug sensitivity prediction was performed using integrated datasets from TCGA, GDSC, and CCLE. To assess the therapeutic potential and underlying mechanisms of combining the CDK inhibitor AZD5438 with the MEK1/2 inhibitor PD0325901, we employed a comprehensive panel of HNSCC models, including established cell lines, orthotopic mouse tumor models, and patient-derived organoids (PDOs). Lipid nanoparticles (LNPs) were engineered to co-deliver both agents into the same cancer cell populations. The tumor secretome was profiled using biotinylation coupled with liquid chromatography-mass spectrometry (LC-MS). Molecular alterations were examined by immunofluorescence, immunohistochemistry, ELISA, flow cytometry, and Western blot. Our bioinformatics analysis identified AZD5438 and PD0325901 as two of thirteen candidate drugs whose sensitivity is consistently associated with the five most frequently mutated genes in HPV (-) HNSCC. Notably, among these candidates, AZD5438 and PD0325901 exhibited the lowest correlation in their sensitivity profiles, suggesting complementary mechanisms of action. In experimental models, the combination of AZD5438 and PD0325901 not only outperformed either monotherapy in suppressing tumor growth but also augmented CD8⁺ T cell-mediated antitumor immunity by promoting caspase-8/gasdermin E-dependent pyroptosis. Furthermore, in both orthotopic tumor-bearing mice and PDOs, the LNP-encapsulated drug combination produced significantly greater therapeutic efficacy compared with the free drug formulation. Our findings indicate that the combination of AZD5438 and PD0325901 holds therapeutic potential for the treatment of HPV (-) HNSCC, particularly in tumors with a high mutational burden. By targeting complementary pathways, this combination may improve treatment outcomes in this aggressive cancer subtype.

Targeted therapies in cancer are limited by cells exhibiting drug tolerance. We aimed to target drug tolerance in order to delay the development of acquired resistance. In melanoma, tolerance to MAPK pathway inhibitors is associated with loss of SOX10 and an enhanced TEAD transcriptional program. We show that loss of SOX10 is sufficient to up-regulate TEAD targets with dependence on the co-activator, TAZ. Active TAZ is sufficient to mediate tolerance to BRAF inhibitors and MEK inhibitors. We develop two covalent inhibitors, OPN-9643 and OPN-9652, designed to target the central palmitate binding pocket of TEADs. In SOX10-deficient cells, OPN-9643 and OPN-9652 reduce TEAD-dependent reporter activity and expression of TEAD targets, CTGF and CYR61. OPN-9643 and OPN-9652 treatment enhances the inhibitory effects of MAPK-targeted therapies in 2D and 3D growth assays in SOX10 knockout cells and reverses tolerance mediated by active TAZ. In vivo, OPN-9652 delays the onset of acquired resistance to BRAF inhibitors and MEK inhibitors from minimal residual disease. Thus, TAZ-TEAD activity plays an important role in melanoma drug tolerance and the development of acquired resistance.

A high therapeutic index, defined as potent inhibition of oncogenic signaling in tumor cells with minimal effects on normal cells, is critical for effective cancer therapies. Recent advances have introduced diverse RAS-targeting inhibitors, including mutant-specific inhibitors such as KRAS G12C and KRAS G12D, as well as paralog- and state-selective inhibitors. Non-mutant-specific RAS inhibition can be achieved by: (1) guanine nucleotide exchange-OFF inhibitors that indirectly inactivate RAS by targeting SHP2 or SOS1, (2) KRAS-OFF inhibitors that spare NRAS and HRAS, and (3) active-state RAS(ON) inhibitors that directly block binding of effector RAF. However, the signaling inhibition index (SII)-the differential suppression of oncogenic signaling between RAS-mutant and normal cells-remains poorly defined for these approaches. We evaluated the SII for state- and paralog-selective RAS inhibitors across diverse RAS-mutant and RAS-wild-type models. Guanine nucleotide exchange-OFF inhibitors exhibited neutral or negative values, with reduced MAPK suppression in KRAS G12X cells compared to wild-type cells. KRAS G13D models, especially with NF1 loss, showed low sensitivity. SHP2 plus MEK inhibition resulted in low selectivity, and RAS Q61X models were resistant due to MEK inhibitor-induced NRAS reactivation and altered SHP2 conformations. KRAS-OFF inhibitors demonstrated higher selectivity, while active-state RAS(ON) inhibitors showed broader activity but narrow selectivity. Sensitivity to mutant-specific inhibitors largely overlapped with sensitivity to state-selective agents, suggesting that most RAS-mutant tumors will respond poorly to any currently available RAS inhibitor. Implications: Determining the signaling inhibition index (SII) can inform the design and clinical application of RAS-targeted therapies to improve tumor selectivity and therapeutic outcomes.

Background: Inhibitors of BRAF (BRAFi) and MEK (MEKi) are often used in advanced BRAF V600E -mutated thyroid cancer (BRAFm-TC), and at least one drug combination is FDA-approved. However, cardiovascular (CV) adverse effects, including hypertension (HTN), are increasingly recognized. Research Question: We examined the incidence of new or worsening HTN during treatment with BRAFi±MEKi and the associated baseline risk factors in patients with BRAFm-TC. Methods: This single-center retrospective cohort study included patients with BRAFm-TC treated with therapeutic-intent BRAFi±MEKi from Jan 2016-Mar 2024. Development of HTN was defined by initiation of new antihypertensives in patients without a history of HTN, up-titration of existing or addition of new antihypertensives in pre-existing HTN, or documentation of elevated blood pressures (BP≥140/90) in notes. Results: Among 245 patients with a median follow-up of 35.9 months (95%CI 31.4-41.2) (Table 1), new or worsening HTN occurred in 34 patients (13.9%) (Fig. 1). Four patients (1.6%) were diagnosed with new HTN at a median of 6.13 months, and 30 (12.2%) with worsening of pre-existing HTN at a median of 5.44 months. Univariate predictors of HTN risk were anaplastic thyroid cancer histology, history of asymptomatic coronary artery disease (CAD), pre-existing HTN, hyperlipidemia, and moderate to high/very high cardiotoxicity risk by the HFA/ICOS risk score. On multivariable analysis, history of asymptomatic CAD (HR 9.23, 95%CI 2.19–38.87; sHR 8.96, 95%CI 2.94–27.26) and pre-existing HTN (HR 4.38, 95%CI 1.54–12.44; sHR 4.47, 95%CI 1.61–12.37) remained associated with HTN development. During follow-up, HTN led to dose adjustments or switching of BRAF/MEKi in two and one patients, respectively, and treatment interruption or early discontinuation due to BRAF/MEKi-associated HTN occurred in one patient. Amongst 34 patients with incident HTN, 11 discontinued the medication for various reasons throughout the study; in 91% of these cases, HTN was reversible. Of the 23 patients who remained on BRAF/MEKi therapy, HTN was effectively controlled with antihypertensive therapy. Conclusion: New or worsening HTN was noted in one in eight individuals with BRAFm-TC after initiation of BRAFi±MEKi. Pre-existing HTN and asymptomatic CAD were independently associated with the risk of developing or worsening HTN, highlighting the need for baseline CV risk assessment and close BP monitoring during treatment to allow safer use of these agents.

Introduction: Exercise is a cornerstone of cardiovascular health, yet not all individuals can engage in sufficient physical activity. Identifying pharmacological agents that mimic exercise-induced molecular adaptations offers a promising strategy for disease prevention. Here, we integrate transcriptomic data from the Molecular Transducers of Physical Activity Consortium (MoTrPAC)—a multi-omics effort characterizing exercise responses—including human skeletal muscle after acute exercise (0-24h), and both acute and endurance training (1-8 weeks) in rat heart and skeletal muscle. These are combined with the Library of Integrated Network-Based Cellular Signatures (LINCS), which catalogs drug-induced transcriptional responses in 292 human cell lines exposed to 20,272 compounds. Through this integrative approach, we aim to identify compounds that replicate transcriptional effects of endurance exercise. Methods: To address transcriptomic differences between tissues and cell lines, we developed a pipeline combining functional and regulatory analyses. We assessed pathway enrichment via FGSEA and inferred transcription factor (TF) activity using VIPER and DoRothEA (Figure 1A). Shared pathways and upstream regulators were integrated into a mimetic score ranking candidate drugs by their functional and regulatory similarity to exercise. Results: We identified between 600–800 candidate mimetics for skeletal muscle in acute human and rat responses, as well as during endurance training. Notably, predicted mimetics aligned well between species (Figure 1B). Among top hits, midodrine, an α1-adrenergic agonist investigating for its cardioprotective properties, matched 24h post-exercise signatures in both species and activated TFs linked to mitochondrial function, vascular remodeling, and metabolism (FOXP1, CREB1). PD-0325901, a MEK inhibitor, showed strong similarity to early phases (15–45 min), inducing early-response TFs (FOS, HIF1A, RELA), and reflected endurance training upregulation of oxidative phosphorylation. Mimetic profiles from rat heart clustered with muscle at matched timepoints, highlighting the potential to extend heart-based predictions to humans via conserved signatures (Figure 1C). Conclusion: This integrative analysis identifies candidate compounds that mimic distinct phases of exercise-induced molecular remodeling. Ongoing validation in cardiac models aims to translate these findings into cardiovascular contexts.

Calcific aortic stenosis (CAS) is the most common valvular disease in the elderly, with no approved pharmacological treatment to slow or reverse its progression. This study combined a systematic literature review (38 human-only studies, PRISMA criteria) with transcriptomic analysis of publicly available datasets (GSE51472 and GSE12644), including 35 human aortic valve samples (15 control, 15 calcified, 5 sclerotic). Differential expression was assessed using the Limma package, applying FDR correction (padj < 0.01) and fold change threshold (|FC| ≥ 1). Key genes were identified based on significant overexpression and biological relevance. RUNX2, IBSP, and SPP1 emerged as central regulators linked to osteogenic transdifferentiation, immune modulation, and extracellular matrix remodeling. KEGG pathway analysis showed enrichment in ECM-receptor interaction, PI3K-Akt signaling. Coexpression and protein-protein interaction networks revealed strong functional clustering of these genes. ROC curve analysis yielded high diagnostic performance: AUC values were 0.79 (RUNX2), 0.65 (IBSP), and 0.75 (SPP1), indicating robust classification of diseased versus normal tissue. Expression levels rose progressively across control, calcified, and sclerotic valve samples. Drug repurposing candidates were identified targeting these molecules. MEK inhibitors (trametinib, selumetinib) downregulate RUNX2 via MAPK/ERK pathway inhibition. Epigenetic modulators (vorinostat, valproic acid) could suppress RUNX2 transcriptionally. The integrin antagonist cilengitide blocks αvβ3, disrupting IBSP/SPP1-mediated signaling. While these agents are approved for oncology or neurology, their utility in valve calcification remains investigational. In summary, this study highlights RUNX2, IBSP, and SPP1 as transcriptomic biomarkers and actionable therapeutic targets in CAS. Their expression profiles, biological roles, and druggability make them high-priority candidates for future diagnostic tools and targeted interventions in a disease currently reliant on surgical replacement.

The MET exon 14 skipping mutation (named METex14Del) described in lung cancer leads to prolonged activation of signaling pathways and aberrant cell responses, but the link between HGF signaling and cell responses remains unclear. A putative lung cancer regulatory network of influential transcription factors was constructed from the transcriptomes of lung cancer cell lines. Transcriptomic data from METex14Del-expressing cells, stimulated or not by HGF, were mapped onto this lung cancer reference network and revealed activation of a major regulatory node composed mainly by the highly influential transcription factors ETS1, FOSL1 and SMAD3. HGF activation of METex14Del receptor induced the expression and phosphorylation of these three master regulators and the expression of their predicted target genes involved in migration and invasion. All these molecular and biological effects were inhibited by trametinib, a MEK inhibitor, which was potentiated by combination with capmatinib, a MET inhibitor. New mapping with transcriptomic data from trametinib-treated METex14Del cells validated the key role of the RAS-ERK pathway signaling in the activation of ETS1, FOSL1 and SMAD3 regulators and the induction of their target genes in HGF-activated METex14Del receptor. Thus, we report an original and powerful strategy to uncover key regulators, including transcription factors that have not been widely described in METex14Del signaling, such as SMAD3. These factors are activated by specific signaling pathways and could provide a novel therapeutic strategy involving a combination of receptor and signaling inhibitors.

Kaposiform lymphangiomatosis (KLA) is a rare and aggressive disease caused by a somatic activating NRAS mutation (p.Q61R) in lymphatic endothelial cells (LECs). The development of new therapeutic avenues is hampered by the lack of animal models faithfully replicating the clinical manifestations of KLA. Here, we established a novel zebrafish model of KLA by conditionally expressing the human NRAS mutation in venous and lymphatic ECs. Mutant embryos recapitulate key clinical features of KLA, including dilated lymphatics and pericardial edema, which are reversed by trametinib, a MEK inhibitor used in KLA treatment. Leveraging this model in combination with an AI-based high-throughput drug screening platform, we identify cabozantinib, a tyrosine kinase inhibitor, and GSK690693, a competitive pan-Akt kinase inhibitor, as promising candidates for treating KLA. Notably, both drugs normalized sprouting and migration of cultured LECs from a KLA patient. Overall, our novel zebrafish model provides a powerful platform to dissect KLA pathogenesis and identify new therapeutic avenues.

Metastatic melanoma, the most aggressive form of skin cancer, accounts for the majority of skin cancer-related deaths. While targeted kinase inhibitors have improved outcomes for patients with BRAF-mutated melanomas, their efficacy is often short-lived, and effective treatments for other mutations, such as NRAS, remain scarce. To address this clinical need, we investigated the combination of the novel panRAF inhibitor, brimarafenib, and the MEK inhibitor, mirdametinib, both of which target the MAPK pathway downstream of NRAS. This study demonstrates the efficacy of this combination in NRAS-mutated melanoma and is currently also investigated in a phase I/IIa clinical study. Invitro, the brimarafenib and mirdametinib combination exhibited synergistic effects, significantly inhibiting the growth of patient-derived NRAS-mutated melanoma cell lines. A colony formation assay showed that this combination prevented the emergence of drug-resistant clones, suggesting a strong potential to reduce disease relapse. Transcriptional and proteomic analyses revealed that the observed growth inhibition was due to modulation of MAPK signaling and induction of apoptosis. Invivo studies further validated these findings, showing that the combination treatment inhibited tumor growth and significantly prolonged survival in mouse models bearing patient-derived NRAS-mutated melanoma tumors. Given the tolerability of this combination invivo, our results suggest that brimarafenib and mirdametinib represent a promising therapeutic strategy for patients with NRAS-mutated melanomas and potentially other RAS-mutated solid tumors.

Langerhans cell histiocytosis (LCH) is a rare malignancy driven by MAPK pathway activation and often involves BRAF V600E mutations. Targeted therapy with trametinib, a MEK inhibitor, is a promising alternative to conventional chemotherapy. We retrospectively analyzed the records of patients treated with trametinib either at relapse or as front-line therapy between 2020 and 2024. Fifteen pediatric patients received trametinib either at diagnosis (n = 6), relapse (n = 7), or due to chemotherapy intolerance (n = 2). Molecular testing identified MAPK pathway mutations in 11 patients. The median age at treatment initiation was 5years (range: 0.1-16.5). Notably, five of these patients started trametinib before the age of 1. The median treatment duration was 2.2years (range: 0.1-4.7years). All 15 patients achieved favorable responses without concerns regarding growth and development. The adverse effects included rash (40%) and diarrhea (13%), which were all mild and were managed with temporary dose adjustments. A self-weaning dosing strategy minimized long-term exposure while maintaining disease control. Our data suggest that trametinib is a safe and effective therapy for pediatric LCH with broad efficacy and tolerability. However, prospective studies are needed to confirm these findings and refine targeted treatment protocols.

MAPK and PKA participate in the JEG-3cell steroidogenesis.

P074 Possible BRAF and MEK inhibitor–associated myositis presenting with Raynaud’s phenomenon in a patient with metastatic melanoma

Brain arteriovenous malformations (bAVMs) are rare but potentially devastating cerebrovascular lesions. Activating KRAS mutations are common in sporadic bAVMs, but their clinical implications remain unclear. The aim of this study was to investigate a novel therapeutic strategy for hemorrhagic bAVMs based on dual inhibition of the mitogen-activated protein kinase (MAPK) and vascular endothelial growth factor (VEGF) pathways using an engineered mouse model with a titratable KRASG12V-GFP transgene. The AAV-BR1-CAG vector was used to deliver a KRASG12V-GFP transgene specifically to cerebral endothelial cells. Mice received 5 × 107 to 5 × 1010 genome copies of the vector, and bAVM formation, intracerebral hemorrhage (ICH), and overall survival were assessed. Mice with established hemorrhagic bAVMs were subsequently treated with trametinib (MEK inhibitor) or RMC-7977 (RAS inhibitor), with or without an anti-mouse VEGF antibody, starting 4 weeks after viral delivery. Overall survival was assessed. Selective overexpression of KRASG12V-GFP in cerebral endothelial cells led to the formation of bAVMs in a dose-dependent manner. Mice that received the highest transgene dose developed significantly more bAVMs, exhibited a higher ICH burden, and had worse overall survival compared with those that received lower transgene doses. In mice receiving the highest transgene dose, trametinib alone modestly improved the median overall survival (8.4 weeks vs 6.4 weeks, p = 0.049), while single-agent RMC-7977 showed no significant benefit. Anti-VEGF therapy alone reduced survival (6.9 weeks vs 9.6 weeks, p = 0.044). However, combination therapy with trametinib or RMC-7977 and anti-VEGF antibody significantly prolonged survival, with the most pronounced benefit seen in the RMC-7977 plus anti-VEGF group (13.1 weeks vs 6.7 weeks in controls, p = 0.024). Our findings suggest that, in addition to promoting bAVM formation, KRAS mutations in cerebral endothelial cells might be causally implicated in bAVM rupture. Additionally, concomitant inhibition of the MAPK and VEGF pathways could be a promising novel therapeutic strategy for KRAS-mutated bAVMs.

Fibrosis is a significant barrier to drug delivery in pancreatic ductal adenocarcinoma (PDAC) and contributes to its dismal prognosis. Pancreatic stellate cells (PSCs) drive fibrosis by excessively secreting extracellular matrix proteins such as collagen I. Collagen I is thought to physically obstruct the delivery of macromolecules, such as albumin, antibodies, and nanomedicines. Apart from its structural role, collagen signals through dedicated cell surface receptors, such as the discoidin domain receptors (DDR) 1/2. However, whether and how collagen signaling contributes to fibrotic barrier generation remains uncharacterized. Here, a 3D culture model of PDAC fibrosis constructed from patient PSCs is used to assess the contribution of DDR1/2-mediated collagen signaling. DDR1/2 inhibition diminishes collagen I expression in PSCs to enhance macromolecular delivery. Moreover, MEK inhibitors exacerbate the fibrotic barrier by up-regulating collagen I, an effect reversed by inhibiting DDR1/2. Through isoform-specific targeting, inhibiting DDR1, but not DDR2, is shown to be effective. Downstream of DDR, the involvement of the PI3K/AKT/mTOR pathway is demonstrated, particularly alternative mTOR complexes involving MEAK7 and GIT1. Altogether, the results show in vitro that DDR1-mediated collagen signaling exacerbates the fibrotic barrier and may be targeted to enhance macromolecular drug delivery in PDAC.

Combined MEK and YAP Inhibition in a Mouse Model of Neuroblastoma: A Promising Approach for Minimal Residual Disease.

Fraxetin inhibits TNFα-mediated synoviocyte activation and attenuates disease progression in a rat model of rheumatoid arthritis.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder associated with central nervous system gliomas, most frequently optic pathway gliomas; however, oligodendrogliomas in the setting of NF1 are exceedingly rare, with no prior documented cases and no established treatment strategies to date. A 53-year-old female with NF1-associated oligodendroglioma experienced multiple recurrences following surgery, radiotherapy, chemotherapy, and targeted therapy. Upon further disease progression, she was treated with a novel combination of thiotepa, bevacizumab, teniposide, and the mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor tunlametinib. After one treatment cycle, the patient achieved a marked reduction in tumor volume, consistent with a complete response (CR). She subsequently completed eight additional cycles of the regimen and has maintained CR. The treatment was well-tolerated, with manageable grade 3 myelosuppression controlled by supportive care. As of June 2025, the patient has achieved a CR with a progression-free survival of 9 months before experiencing disease recurrence. This rare case of NF1-associated oligodendroglioma was managed with thiotepa, bevacizumab, teniposide, and tunlametinib, highlighting the potential of MEK inhibition in NF1-related gliomas.

RNA maturation, particularly splicing, depends on coordinated actions of RNA-binding proteins through post-transcriptional processing and constitutes a central mechanism of gene regulation. Aberrant splicing is associated with various diseases, including cancer. Here, we show that the CoREST complex, in coordination with c-MYC, transcriptionally regulates a subset of RNA processing genes, including those encoding essential small nuclear ribonucleoproteins (snRNPs) required for proper spliceosome function. Genetic depletion or the pharmacological inhibition of the CoREST complex in melanoma cells disrupted spliceosome activity, leading to widespread changes in alternative mRNA isoform expression and reduced cell viability. These splicing alterations were associated with changes in the 2′-O-methylation (Nm) of U1 snRNA, a modification critical for spliceosomal function. The ectopic expression of the nucleolar protein NOLC1, a downstream target of the CoREST complex and known for its role in ribosomal RNA processing, partially rescued viability, splicing patterns, and U1 snRNA methylation in CoREST-deficient melanoma cells. Conversely, NOLC1 depletion sensitized melanoma cells to the MEK inhibitor trametinib, a clinical drug approved for treating advanced melanoma. Together, these findings uncover a novel CoREST-NOLC1 axis which is a transcriptional regulatory mechanism playing a significant role in RNA splicing, highlighting that NOLC1 is a downstream effector of the CoREST complex and a potential therapeutic target for melanoma treatment.