FAK inhibition combined with the RAF-MEK clamp avutometinib overcomes resistance to targeted and immune therapies in BRAF V600E melanoma.

• Tác giả: Sendi R Adame-Garcia, Paola Y Anguiano Quiroz, Andrew E Aplin, Nadia Arang, Antonietta Bacchiocchi, Rodolfo Daniel Cervantes-Villagrana, Silvia Coma, Farhoud Faraji, Fleur M Ferguson, J Silvio Gutkind, Ruth Halaban, Sheri L Holmen, Simone Lubrano, Claudia Martini, Adam Officer, Jonathan A Pachter, Sydney Ramirez, Damiano C Rigiracciolo, Kuniaki Sato, YiYu Wang
• Ngôn ngữ: eng
• Ký hiệu phân loại: 297.1248 Sources of Islam
• Thông tin xuất bản: United States : Cancer cell , 2025
• Bộ sưu tập: NCBI
• ID: 692234

Tóm tắt

 Widespread BRAF mutations result in persistent RAS-RAF-MEK-ERK (MAPK) signaling in melanoma. BRAF (BRAFi) and MEK (MEKi) inhibitors are approved for BRAF V600E melanomas, including those progressing on immunotherapy
  however, rapid resistance to these agents highlights the need for novel strategies. Here, transcriptome analysis of BRAF V600E melanomas from patients resistant to BRAFi and MEKi shows activation of focal adhesion signaling. Consistently, BRAFi, MEKi, and the RAF-MEK clamp avutometinib activate focal adhesion kinase (FAK) in melanoma cells. Mechanistically, inhibition of an MAPK-RhoE (RND3) feedback loop results in the adaptive activation of RhoA-FAK-AKT. In turn, FAK inhibitors (FAKi) exert potent pro-apoptotic activity when combined with MAPK pathway inhibition. FAKi plus avutometinib overcomes resistance in multiple models derived from BRAFi plus MEKi-resistant melanoma patients and immunotherapy-resistant syngeneic mouse models. These findings provide a rationale for the development of avutometinib in combination with FAKi for patients with BRAF V600E melanoma progressing on BRAFi plus MEKi or immunotherapy.