Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China.
Academy of Medical Science, Zhengzhou University, Zhengzhou, China.
Front Immunol. 2023 Aug 18;14:1223433. doi: 10.3389/fimmu.2023.1223433. eCollection 2023.
Three rat sarcoma (RAS) gene isoforms, KRAS, NRAS, and HRAS, constitute the most mutated family of small GTPases in cancer. While the development of targeted immunotherapies has led to a substantial improvement in the overall survival of patients with non-KRAS-mutant cancer, patients with RAS-mutant cancers have an overall poorer prognosis owing to the high aggressiveness of RAS-mutant tumors. KRAS mutations are strongly implicated in lung, pancreatic, and colorectal cancers. However, RAS mutations exhibit diverse patterns of isoforms, substitutions, and positions in different types of cancers. Despite being considered "undruggable", recent advances in the use of allele-specific covalent inhibitors against the most common mutant form of RAS in non-small-cell lung cancer have led to the development of effective pharmacological interventions against RAS-mutant cancer. Sotorasib (AMG510) has been approved by the FDA as a second-line treatment for patients with KRAS-G12C mutant NSCLC who have received at least one prior systemic therapy. Other KRAS inhibitors are on the way to block KRAS-mutant cancers. In this review, we summarize the progress and promise of small-molecule inhibitors in clinical trials, including direct inhibitors of KRAS, pan-RAS inhibitors, inhibitors of RAS effector signaling, and immune checkpoint inhibitors or combinations with RAS inhibitors, to improve the prognosis of tumors with RAS mutations.
三种大鼠肉瘤 (RAS) 基因异构体，KRAS、NRAS 和 HRAS，构成了癌症中小 GTPase 突变最多的家族。虽然针对非 KRAS 突变型癌症的靶向免疫疗法的发展显著提高了患者的总生存率，但由于 RAS 突变型肿瘤的高度侵袭性，RAS 突变型癌症患者的总体预后较差。KRAS 突变强烈暗示了肺癌、胰腺癌和结直肠癌。然而，RAS 突变在不同类型的癌症中表现出不同的异构体、取代和位置模式。尽管被认为是“不可成药”的，但最近在使用针对非小细胞肺癌中最常见 RAS 突变形式的等位基因特异性共价抑制剂方面的进展，导致了针对 RAS 突变型癌症的有效药物干预的发展。Sotorasib（AMG510）已被 FDA 批准作为接受过至少一次先前系统治疗的 KRAS-G12C 突变 NSCLC 患者的二线治疗药物。其他 KRAS 抑制剂也在开发中，以阻断 KRAS 突变型癌症。在这篇综述中，我们总结了小分子抑制剂在临床试验中的进展和前景，包括 KRAS 的直接抑制剂、pan-RAS 抑制剂、RAS 效应信号抑制剂以及免疫检查点抑制剂或与 RAS 抑制剂的联合治疗，以改善 RAS 突变肿瘤的预后。
