Ebright Richard Y, Dilly Julien, Shaw Alice T, Aguirre Andrew J
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
Harvard Medical School, Boston, Massachusetts.
Cancer Discov. 2025 Jul 3;15(7):1325-1349. doi: 10.1158/2159-8290.CD-25-0349.
RAS inhibition has the potential to transform cancer treatment for many patients. The landscape of RAS inhibitor therapies is rapidly evolving, with two mutant-selective KRAS inhibitors now approved and multiple other mutant-selective, pan-KRAS, and pan-RAS inhibitors in development. However, monotherapy efficacy has been limited by primary and acquired resistance. In this article, we review preclinical and clinical data on RAS inhibition in cancer and describe multiple genetic and nongenetic mechanisms of resistance. Moreover, we highlight future opportunities for the design of rational combination therapy strategies, which will ultimately be needed to overcome resistance and enhance the efficacy of these promising treatments.
RAS inhibitors have shown early evidence of efficacy in multiple cancer types, but clinical benefit is limited by acquired resistance. Development of best-in-class inhibitors, with optimal potency, selectivity, and pharmacokinetic properties, as well as effective and tolerable combination therapies will be needed to overcome resistance and maximize the clinical impact of RAS-targeted therapy.
RAS抑制有潜力改变许多患者的癌症治疗方式。RAS抑制剂疗法的格局正在迅速演变，目前已有两种突变体选择性KRAS抑制剂获批，还有多种其他突变体选择性、泛KRAS和泛RAS抑制剂正在研发中。然而，单药治疗的疗效受到原发性和获得性耐药的限制。在本文中，我们回顾了癌症中RAS抑制的临床前和临床数据，并描述了多种耐药的遗传和非遗传机制。此外，我们强调了合理联合治疗策略设计的未来机会，最终需要这些策略来克服耐药性并提高这些有前景治疗的疗效。
RAS抑制剂在多种癌症类型中已显示出早期疗效证据，但临床获益受到获得性耐药的限制。需要开发具有最佳效力、选择性和药代动力学特性的同类最佳抑制剂，以及有效且可耐受的联合疗法，以克服耐药性并最大化RAS靶向治疗的临床影响。
