Abstract 4745: A novel combination therapy targeting RAF, MEK and FAK to overcome skin cutaneous melanoma treatment resistance

Abstract Metastatic melanoma is the most aggressive malignancy of the skin and BRAFV600E mutation is the most common genetic alteration in skin cutaneous melanoma (SKCM). Despite the advent of immune checkpoint inhibition (ICI) immunotherapy, only 40% of patients show long-term responses. As such, combined therapy with BRAF and MEK inhibitors (BRAFi + MEKi) remains the standard of care for BRAFV600E+ SKCM. In the present study, transcriptome analysis of BRAFV600E+ SKCM tumors derived from patients revealed that activation of extracellular matrix signaling, including focal adhesion signaling, is highly enriched in patients who experienced disease progression on BRAFi + MEKi therapy. Consistent with these results, we found increased activation of focal adhesion kinase (FAK) in human BRAFV600E+ SKCM A375 cells treated with BRAFi, MEKi or the RAF/MEK clamp avutometinib. Mechanistically, we discovered that avutometinib-mediated inhibition of the RAF/MEK/ERK pathway decreased RhoE/Rnd3 expression, thereby unleashing RhoA/FAK/AKT signaling. Thus, we hypothesized that FAK activation represents a resistance mechanism to BRAFi + MEKi and that FAK inhibition (FAKi) might overcome resistance to BRAFi/MEKi. Indeed, avutometinib demonstrated synergistic antiproliferative and proapoptotic activity when combined with FAKi in human BRAFV600E+ SKCM A375 cells. Importantly, we found that the combination of FAKi + avutometinib overcame resistance to BRAFi + MEKi in SKCM xenografts and patient-derived cells from SKCM-resistant lesions. Finally, we showed that while BRAFV600E+ SKCM YUMM 1. 7 syngeneic tumors failed to respond to ICI therapy, avutometinib ± FAKi inhibited tumor growth. We observed that tumors treated with avutometinib as single agent eventually developed resistance and escaped growth inhibition, but those treated with combined avutometinib and FAKi displayed durable treatment responses, often with complete tumor regression. These findings provide a rationale for the clinical development of avutometinib with defactinib (FAKi) in patients with BRAFV600E+ cutaneous melanoma following progression on BRAFi + MEKi and/or ICI therapy. Citation Format: Simone Lubrano, Farhoud Faraji, Rodolfo Daniel Cervantes-Villagrana, Sydney Ramirez, Nadia Arang, Adam Officer, Damiano C. Rigiracciolo, Paola Y. Anguiano Quiroz, Antonieta Bacchiocchi, Ruth Halaban, Silvia Coma, Sheri Holmen, Claudia Martini, Jonathan Pachter, Andrew Aplin, J. Silvio Gutkind. A novel combination therapy targeting RAF, MEK and FAK to overcome skin cutaneous melanoma treatment resistance abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4745.