Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) is the most frequently mutated oncogene, occurring in a variety of tumor types. Targeting KRAS mutations with drugs is challenging because KRAS is considered undruggable due to the lack of classic drug binding sites. Over the past 40 years, great efforts have been made to explore routes for indirect targeting of KRAS mutant cancers, including KRAS expression, processing, upstream regulators, or downstream effectors. With the advent of KRAS (G12C) inhibitors, KRAS mutations are now druggable. Despite such inhibitors showing remarkable clinical responses, resistance to monotherapy of KRAS inhibitors is eventually developed. Significant progress has been made in understanding the mechanisms of drug resistance to KRAS-mutant inhibitors. Here we review the most recent advances in therapeutic approaches and resistance mechanisms targeting KRAS mutations and discuss opportunities for combination therapy.

中文翻译：

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靶向 KRAS 突变癌症：从药物治疗到耐药性

Kirsten 大鼠肉瘤病毒癌基因同源物 (KRAS) 是最常发生突变的癌基因，发生在多种肿瘤类型中。用药物靶向 KRAS 突变具有挑战性，因为由于缺乏经典的药物结合位点，KRAS 被认为是不可成药的。在过去的 40 年中，人们努力探索间接靶向 KRAS 突变癌症的途径，包括 KRAS 表达、加工、上游调节因子或下游效应子。随着 KRAS (G12C) 抑制剂的出现，KRAS 突变现在可用于药物治疗。尽管此类抑制剂显示出显着的临床反应，但最终对 KRAS 抑制剂的单一疗法产生了耐药性。在了解 KRAS 突变抑制剂的耐药机制方面取得了重大进展。