Combining FAK Inhibition with the RAF/MEK inhibitor avutometinib overcomes resistance to Targeted and Immune Therapies in Cutaneous Melanoma

Simone Lubrano - University of San Diego California - Università di Pisa
Combining FAK Inhibition with the RAF/MEK inhibitor avutometinib overcomes resistance to Targeted and Immune Therapies in Cutaneous Melanoma

Abstract
Metastatic melanoma is the most aggressive skin cancer, with the BRAF V600E mutation being the most prevalent genetic alteration in cutaneous melanoma. Despite the introduction of immune checkpoint inhibitors (ICI), only 40% of patients achieve long-term responses. Consequently, combined therapy with BRAF and MEK inhibitors (BRAFi + MEKi) remains the standard treatment for BRAFV600E melanoma. Our transcriptome analysis of BRAF V600E melanomas revealed a significant activation of extracellular matrix signaling, including focal adhesion signaling, in patients that experienced disease progression on BRAFi + MEKi therapy. Aligned with these results, we observed increased activation of focal adhesion kinase (FAK) in human BRAFV600E A375 melanoma cells treated with BRAFi, MEKi, or the RAF/MEK clamp avutometinib. Mechanistically, avutometinib-mediated inhibition of the RAF/MEK/ERK pathway reduced RhoE/Rnd3 expression, thereby enhancing RhoA/FAK/AKT signaling. This led us to hypothesize that FAK activation represents a resistance mechanism to RAF/MEK/ERK pathway inhibition, and that FAK inhibition (FAKi) could potentially overcome this resistance. Supporting this, avutometinib showed synergistic antiproliferative and proapoptotic effects when combined with FAKi in multiple human BRAFV600E melanoma cell lines. Notably, the combination of FAKi and avutometinib overcame resistance to BRAFi + MEKi in melanoma xenografts and patient-derived cells from resistant lesions. Additionally, while BRAFV600E YUMM 1.7 syngeneic melanoma lesions did not respond to ICI therapy, avutometinib with or without FAKi inhibited tumor growth. While tumors treated with avutometinib alone eventually developed resistance, those treated with the combination of avutometinib and FAKi exhibited durable responses, often with complete tumor regression. These findings support the clinical development of avutometinib with the FAK inhibitor defactinib for patients with BRAFV600E melanomas who have progressed on BRAFi + MEKi and/or ICI therapy.

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