Department of Structural Biology, Genentech Inc., South San Francisco, California 94080.
Department of Discovery Oncology, Genentech Inc., South San Francisco, California 94080.
Cold Spring Harb Perspect Med. 2018 Nov 1;8(11):a031492. doi: 10.1101/cshperspect.a031492.
Despite decades of extensive drug discovery efforts, there are currently no targeted therapies approved to treat KRAS mutant cancers. In this review, we highlight the challenges and opportunities in targeting KRAS mutant tumors through inhibition of mitogen-activated protein kinase (MAPK) signaling with conformation-specific kinase inhibitors. Through structural analysis and mechanistic studies with BRAF and mitogen-activated protein kinase (MEK) inhibitors, we describe how kinase-dependent and -independent functions of MAPK signaling components regulate KRAS-driven tumorigenesis and how these insights can be used to treat RAS mutant cancers with small molecule kinase inhibitors.
尽管经过几十年的广泛药物研发努力，目前尚无针对 KRAS 突变癌症的靶向治疗方法获得批准。在这篇综述中，我们通过抑制有丝分裂原活化蛋白激酶（MAPK）信号传导来强调针对 KRAS 突变肿瘤的挑战和机遇，使用构象特异性激酶抑制剂。通过对 BRAF 和丝裂原活化蛋白激酶（MEK）抑制剂的结构分析和机制研究，我们描述了 MAPK 信号传导成分的激酶依赖性和非依赖性功能如何调节 KRAS 驱动的肿瘤发生，以及如何利用这些见解使用小分子激酶抑制剂治疗 RAS 突变癌症。
