FAK抑制联合RAF-MEK钳夹阿武替尼克服了BRAF V600E黑色素瘤对靶向和免疫疗法的耐药性，这一成果由加州大学J. Silvio Gutkind研究组经过不懈努力而取得。相关论文发表在2025年2月27日出版的《癌细胞》杂志上。

广泛的BRAF突变导致黑色素瘤中持续的RAS-RAF-MEK-ERK （MAPK）信号传导。BRAF （BRAFi）和MEK （MEKi）抑制剂被批准用于BRAF V600E黑色素瘤，包括那些正在进行免疫治疗的黑色素瘤；然而，对这些药物的快速耐药性突出了对新策略的需求。对BRAFi和MEKi耐药患者的BRAF V600E黑色素瘤的转录组分析显示，灶性粘连信号被激活。BRAFi， MEKi和RAF-MEK钳avutometinib激活黑色素瘤细胞中的局灶黏附激酶（FAK）。从机制上讲，抑制MAPK-RhoE （RND3）反馈回路导致RhoA-FAK-AKT的适应性激活。反过来，FAK抑制剂（FAKi）在与MAPK通路抑制结合时发挥强大的促凋亡活性。FAKi plthem avutometinib克服了来自BRAFi plthem meki耐药黑色素瘤患者和免疫治疗耐药同基因基因模型的多种模型的耐药。这些发现为开发avutometinib联合FAKi治疗BRAF V600E黑色素瘤患者提供了理论依据，BRAF V600E黑色素瘤患者在BRAFi、MEKi或免疫治疗中进展。

附：英文原文

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

Author: Simone Lubrano, Rodolfo Daniel Cervantes-Villagrana, Farhoud Faraji, Sydney Ramirez, Kuniaki Sato, Sendi R. Adame-Garcia, Adam Officer, Nadia Arang, Damiano C. Rigiracciolo, Paola Y. Anguiano Quiroz, Claudia Martini, YiYu Wang, Fleur M. Ferguson, Antonietta Bacchiocchi, Ruth Halaban, Silvia Coma, Sheri L. Holmen, Jonathan A. Pachter, Andrew E. Aplin, J. Silvio Gutkind

Issue&Volume: 2025-02-27

Abstract: 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.

DOI: 10.1016/j.ccell.2025.02.001

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00053-4