MEK Inhibitor / Allist - LARVOL DELTA

The MEK inhibitor trametinib incurs mitochondrial injury and induces innate immune responses in the mouse heart. (PubMed, Sci Adv) - "In multiple rodent and human cardiomyocyte platforms, Trm diminished mitochondrial respiratory capacity at nanomolar concentrations, but this lesion was reversed by expression of a phosphomimetic signal transducer and activator of transcription 3-S727 construct. We also found that Trm induced mitochondrial dysfunction in some but not all cancer cell lines, identifying a previously unrecognized effect that could contribute to Trm's anticancer efficacy."

Journal • Preclinical • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Melanoma • Metabolic Disorders • Oncology • Solid Tumor • BRAF • STAT3 • STING

A phase I trial of binimetinib plus hydroxychloroquine in patients with previously treated metastatic pancreatic cancer. (ASCO 2025) - P1 | "We hypothesized that blockade of autophagy with hydroxychloroquine (HCQ) can overcome therapeutic resistance to MEK inhibition with binimetinib (bini) and lead to clinical benefit in patients (pts) with previously treated, KRAS-mutant metastatic pancreatic ductal adenocarcinoma (PDAC). Bini + HCQ demonstrated a challenging toxicity profile and limited clinical activity in a heavily pretreated cohort of metastatic PDAC pts. Minimal efficacy was observed in this treatment-refractory population; however, dual MEK and autophagy inhibition may warrant further study in earlier-line settings, potentially with more tolerable drug candidates and guided by biomarker selection."

Clinical • Metastases • P1 data • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Renal Disease • Solid Tumor • KRAS

The Role of Immune Activation in Trametinib-Induced Cardiomyopathy (AHA 2023) - "Introduction: Trametinib (Trm) is a highly selective inhibitor of MEK1/2, downstream targets of the RAS signaling pathway that has been used widely for the treatment of BRAF V600E/K-mutant melanoma. Trm treatment is associated with cardiomyopathy in up to 20% of patients. Understanding the mechanisms driving this disease pathogenesis may help reduce likelihood of adverse cardiac events associated with future MEK inhibitor therapy used alone or in combination with other agents. Our novel findings suggest that Trm causes immune dysregulation and inflammation in the heart."

Breast Cancer • Cardiomyopathy • Cardiovascular • Colorectal Cancer • Genito-urinary Cancer • Hematological Malignancies • Leukemia • Melanoma • Oncology • Prostate Cancer • Solid Tumor • Triple Negative Breast Cancer • BRAF • CD68

BRAF/MEK combo shows long-term efficacy in melanoma (MDedge Hematology & Oncology) - "The findings present good news, but the combination still doesn't represent the best first-line option, according to Ryan Sullivan, MD, who wrote an accompanying editorial....To improve matters, Dr. Sullivan suggested that they could be used in the adjuvant setting, where disease burden is lower. He noted that dabrafenib and trametinib are approved for resected stage 3 melanoma and showed similar efficacy to immunotherapy in that setting. Immunotherapy retains efficacy after BRAF-targeted therapy."

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