Disarming cancer resistance: FAK as a therapeutic target

The FDA recently granted accelerated approval of the small-molecule focal adhesion kinase (FAK) inhibitor (FAKi, defactinib) in combination with a RAF-MEK clamp inhibitor (avutometinib) for KRAS-mutated low-grade serous ovarian cancer developed by Verastem Inc. This milestone moment represents a long journey in FAKi development, from initial findings of limited single-agent activity to orally delivered FAKi effects that can sensitize solid tumors to chemotherapy, radiotherapy, and immunotherapy treatments. In this study, we review a short history of FAK, summarize ongoing combinatorial clinical trials, discuss potential mechanisms of action, and highlight studies showing that FAK activation is a chemo- and mechano-sensitive signaling hub driving tumor adaptive changes. Targeting FAK disarms tumor resistance through multiple mechanisms, which supports new biological insights and future clinical combinations.