Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK-YAP Signaling.
Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK-YAP Signaling.
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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。
DOI：
10.1002/advs.202100250
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Ren R
中科院分区：
文献类型：
--
作者：
Zhang B;Zhang Y;Zhang J;Liu P;Jiao B;Wang Z;Ren R
KRAS突变是癌症发展最普遍的遗传驱动因素之一，但KRAS突变直到最近才被认为是不可治疗的。目前正在进行针对KRAS G12 C突变的药物试验，但由于长期使用而获得的耐药性已经成为一个主要问题。在此，证明了KRAS G12 C抑制诱导局灶性粘附激酶（FAK）的持续活化，并显示包含KRAS G12 C抑制和FAK抑制剂（IN 10018）的组合疗法实现协同抗癌作用。同时还能降低耐药程度。检查KRAS G12 C突变癌症的多种CDX和PDX模型，并且一致地观察到来自组合疗法的协同益处。从机制上讲，发现FAK-YAP信号传导异常和FAK相关的纤维化都影响KRAS G12 C抑制剂耐药性的发展。因此，这项研究阐明了癌症对KRAS G12 C抑制剂治疗的耐药性机制，以及改善KRAS G12 C突变癌症治疗结果的创新联合疗法。在此，描述了通过KRAS G12 C和FAK抑制的组合用于KRAS G12 C突变癌症的治疗策略。从机制上讲，异常的FAK-雅普信号传导阻碍了KRAS G12 C抑制剂的益处。KRAS G12 C和FAK抑制剂的组合产生协同抗肿瘤作用，为KRAS G12 C突变型癌症提供了获得强化和延长治疗结果的方案。
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. Here, a therapeutic strategy is described for KRAS G12C mutant cancers by the combination of KRAS G12C and FAK inhibition. Mechanistically, the aberrant FAK‐YAP signaling hampers benefits from KRAS G12C inhibitors. The combination of KRAS G12C and FAK inhibitors produces synergistic antitumor effects, providing a regimen to obtain strengthened and prolonged treatment outcomes for KRAS G12C mutant cancers.
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影响因子：
14.9
作者：
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作者：
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KRAS突变肺癌的当前疗法。
DOI：
10.1007/s10555-020-09903-9
发表时间：
2020-12
期刊：
Cancer metastasis reviews
影响因子：
--
作者：
Ghimessy A;Radeczky P;Laszlo V;Hegedus B;Renyi-Vamos F;Fillinger J;Klepetko W;Lang C;Dome B;Megyesfalvi Z
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Megyesfalvi Z