Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling,Advanced Science

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Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling
Advanced Science ( IF 14.3 ) Pub Date : 2021-06-20 , DOI: 10.1002/advs.202100250
Baoyuan Zhang ₁ , Yan Zhang ₁ , Jiangwei Zhang ₂ , Ping Liu ₁ , Bo Jiao ₁ , Zaiqi Wang ₂ , Ruibao Ren ₁

Affiliation

KRAS mutation is one of the most prevalent genetic drivers of cancer development, yet KRAS mutations are until very recently considered undruggable. There are ongoing trials of drugs that target the KRAS G12C mutation, yet acquired drug resistance from the extended use has already become a major concern. Here, it is demonstrated that KRAS G12C inhibition induces sustained activation of focal adhesive kinase (FAK) and show that a combination therapy comprising KRAS G12C inhibition and a FAK inhibitor (IN10018) achieves synergistic anticancer effects. It can simultaneously reduce the extent of drug resistance. Diverse CDX and PDX models of KRAS G12C mutant cancer are examined and synergistic benefits from the combination therapy are consistently observed. Mechanistically, it is found that both aberrant FAK–YAP signaling and FAK-related fibrogenesis impact on the development of KRAS G12C inhibitor resistance. This study thus illustrates the mechanism of resistance of cancer to the treatment of KRAS G12C inhibitor, as well as an innovative combination therapy to improve treatment outcomes for KRAS G12C mutant cancers.

中文翻译：

粘着斑激酶 (FAK) 抑制与 KRAS G12C 抑制剂通过调节 FAK-YAP 信号传导协同治疗癌症

KRAS 突变是癌症发展最普遍的遗传驱动因素之一，但直到最近 KRAS 突变才被认为是不可治疗的。针对 KRAS G12C 突变的药物试验正在进行中，但因长期使用而产生的耐药性已成为一个主要问题。在此，证明 KRAS G12C 抑制可诱导局灶粘附激酶 (FAK) 持续激活，并表明包含 KRAS G12C 抑制和 FAK 抑制剂 (IN10018) 的联合疗法可实现协同抗癌作用。同时可以降低耐药程度。对 KRAS G12C 突变癌症的多种 CDX 和 PDX 模型进行了检查，并一致观察到联合治疗的协同效益。从机制上讲，我们发现异常的 FAK-YAP 信号传导和 FAK 相关的纤维形成都会影响 KRAS G12C 抑制剂耐药性的发展。因此，这项研究阐明了癌症对 KRAS G12C 抑制剂治疗产生耐药性的机制，以及改善 KRAS G12C 突变癌症治疗效果的创新联合疗法。

更新日期：2021-08-19

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