University of California Irvine School of Medicine, Orange, CA, USA; Chao Family Comprehensive Cancer Center, Orange, CA, USA; Division of Neurology, Department of Internal Medicine, St. Marianna University, Kawasaki, Japan.
Department of Hematology and Oncology, St. Joseph Mercy Health System, Ann Arbor, MI, USA.
Cancer Treat Rev. 2021 Dec;101:102309. doi: 10.1016/j.ctrv.2021.102309. Epub 2021 Oct 21.
Kirsten rat sarcoma viral oncogene homolog (KRAS) is a proto-oncogene of the RAS-MAPK pathway. KRAS mutations are present in a variety of malignancies including lung, colorectal, and pancreatic cancer. Until the recent approval of sotorasib, a KRAS G12C inhibitor, lack of targeted therapy for KRAS has resulted in poor prognosis of patients with tumors harboring KRAS mutations. While the conditional approval of sotorasib was a major breakthrough for those patients harboring KRAS G12C mutations, G12C only accounts for a fraction of those with KRAS mutations and eventual resistance to G12C inhibitors are unavoidable. This comprehensive review on KRAS inhibitors covers accumulating evidence on not only the G12C inhibitors but also other therapeutic attempts to tackle KRAS including combination therapy as well as direct inhibition with vaccines, adoptive T cell therapy, proteolysis-targeted chimeras (PROTACs) and CRISPR/Cas9.
克蒂森大鼠肉瘤病毒癌基因同源物（KRAS）是 RAS-MAPK 通路的原癌基因。KRAS 突变存在于多种恶性肿瘤中，包括肺癌、结直肠癌和胰腺癌。直到最近 sotorasib（一种 KRAS G12C 抑制剂）获得批准，针对 KRAS 的靶向治疗的缺乏导致了携带 KRAS 突变的肿瘤患者的预后不良。虽然 sotorasib 的有条件批准对那些携带 KRAS G12C 突变的患者来说是一个重大突破，但 G12C 仅占 KRAS 突变患者的一部分，对 G12C 抑制剂的最终耐药性是不可避免的。这篇关于 KRAS 抑制剂的综述涵盖了不仅针对 G12C 抑制剂的累积证据，还涵盖了针对 KRAS 的其他治疗尝试，包括联合治疗以及使用疫苗、过继性 T 细胞疗法、蛋白水解靶向嵌合体（PROTACs）和 CRISPR/Cas9 进行直接抑制。
