Recently reported to be effective in patients with lung cancer, KRAS^G12C inhibitors bind to the inactive, or guanosine diphosphate (GDP)–bound, state of the oncoprotein and require guanosine triphosphate (GTP) hydrolysis for inhibition. However, KRAS mutations prevent the catalytic arginine of GTPase-activating proteins (GAPs) from enhancing an otherwise slow hydrolysis rate. If KRAS mutants are indeed insensitive to GAPs, it is unclear how KRAS^G12C hydrolyzes sufficient GTP to allow inactive state–selective inhibition. Here, we show that RGS3, a GAP previously known for regulating G protein–coupled receptors, can also enhance the GTPase activity of mutant and wild-type KRAS proteins. Our study reveals an unexpected mechanism that inactivates KRAS and explains the vulnerability to emerging clinically effective therapeutics.

中文翻译：

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G 蛋白信号调节器 RGS3 增强 KRAS 的 GTPase 活性

^{最近据报道，KRAS G12C}抑制剂对肺癌患者有效，它与癌蛋白的非活性或鸟苷二磷酸 (GDP) 结合状态结合，需要三磷酸鸟苷 (GTP) 水解来抑制。然而，KRAS 突变阻止 GTP 酶激活蛋白 (GAP) 的催化精氨酸提高原本缓慢的水解速率。如果 KRAS 突变体确实对 GAP 不敏感，目前尚不清楚 KRAS ^{G12C是如何}水解足够的 GTP 以允许非活性状态选择性抑制。在这里，我们展示了 RGS3，一种以前已知用于调节 G 蛋白偶联受体的 GAP，也可以增强突变型和野生型 KRAS 蛋白的 GTPase 活性。我们的研究揭示了一种使 KRAS 失活的意外机制，并解释了对新兴临床有效疗法的脆弱性。