治疗转移性结直肠癌的 KRAS G12C 抑制剂

IF 3.3 3区 医学 Q2 ONCOLOGY
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引用次数: 0

摘要

KRAS 基因突变是结直肠癌的主要致病因素,长期以来一直是药物研发工作的重点。经过漫长的临床前研究,通过 G12C 等位基因抑制 KRAS 终于成为治疗现实。与 NSCLC 不同的是,KRAS 抑制剂在 CRC 中的早期研究难以证明其单药活性。通过对这些组织特异性治疗差异的研究,人们对 MAPK 信号传导的复杂性以及 KRAS 抑制的各种适应性反馈反应有了更深入的了解。表皮生长因子受体再激活已成为 KRAS 抑制剂单药治疗的主要耐药机制。因此,该领域已转向具有良好疗效的表皮生长因子受体/KRAS双重阻断疗法。尽管在治疗 KRAS G12C 突变的 CRC 方面取得了重大进展,但新的挑战即将到来。替代 RTK 的重新激活和无数获得性分子耐药机制改变了治疗目标。本综述将重点介绍针对 KRAS G12C 变异的 CRC 的历史和当代临床策略,并强调克服治疗挑战的未来方向。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
KRAS G12C Inhibitors in the Treatment of Metastatic Colorectal Cancer

KRAS mutations contribute substantially to the overall colorectal cancer burden and have long been a focus of drug development efforts. After a lengthy preclinical road, KRAS inhibition via the G12C allele has finally become a therapeutic reality. Unlike in NSCLC, early studies of KRAS inhibitors in CRC struggled to demonstrate single agent activity. Investigation into these tissue-specific treatment differences has led to a deeper understanding of the complexities of MAPK signaling and the diverse adaptive feedback responses to KRAS inhibition. EGFR reactivation has emerged as a principal resistance mechanism to KRAS inhibitor monotherapy. Thus, the field has pivoted to dual EGFR/KRAS blockade with promising efficacy. Despite significant strides in the treatment of KRAS G12C mutated CRC, new challenges are on the horizon. Alternative RTK reactivation and countless acquired molecular resistance mechanisms have shifted the treatment goalpost. This review focuses on the historical and contemporary clinical strategies of targeting KRAS G12C alterations in CRC and highlights future directions to overcome treatment challenges.

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来源期刊
Clinical colorectal cancer
Clinical colorectal cancer 医学-肿瘤学
CiteScore
5.50
自引率
2.90%
发文量
64
审稿时长
27 days
期刊介绍: Clinical Colorectal Cancer is a peer-reviewed, quarterly journal that publishes original articles describing various aspects of clinical and translational research of gastrointestinal cancers. Clinical Colorectal Cancer is devoted to articles on detection, diagnosis, prevention, and treatment of colorectal, pancreatic, liver, and other gastrointestinal cancers. The main emphasis is on recent scientific developments in all areas related to gastrointestinal cancers. Specific areas of interest include clinical research and mechanistic approaches; drug sensitivity and resistance; gene and antisense therapy; pathology, markers, and prognostic indicators; chemoprevention strategies; multimodality therapy; and integration of various approaches.
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