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Abstract：
Kirsten rat sarcoma virus oncogene homolog (KRAS) is the most frequently mutated oncogene in human cancer. In colorectal cancer (CRC), KRAS mutations are present in more than 50% of cases, and the KRAS glycine-to-cysteine mutation at codon 12 (KRAS G12C) occurs in up to 4% of patients. This mutation is associated with short responses to standard chemotherapy and worse overall survival compared to non-G12C mutations. In recent years, several KRAS G12C inhibitors have demonstrated clinical activity, although all patients eventually progressed. The identification of negative feedback through the EGFR receptor has led to the development of KRAS inhibitors plus an anti-EGFR combination, thus boosting antitumor activity. Currently, several KRAS G12C inhibitors are under development, and results from phase I and phase II clinical trials are promising. Moreover, the phase III CodeBreaK 300 trial demonstrates the superiority of sotorasib-panitumumab over trifluridine/tipiracil, establishing a new standard of care for patients with colorectal cancer harboring KRAS G12C mutations. Other combinations such as adagrasib-cetuximab, divarasib-cetuximab, or FOLFIRI-panitumumab-sotorasib have also shown a meaningful response rate and are currently under evaluation. Nonetheless, most of these patients will eventually relapse. In this setting, liquid biopsy emerges as a critical tool to characterize the mechanisms of resistance, consisting mainly of acquired genomic alterations in the MAPK and PI3K pathways and tyrosine kinase receptor alterations, but gene fusions, histological changes, or conformational changes in the kinase have also been described. In this paper, we review the development of KRAS G12C inhibitors in colorectal cancer as well as the main mechanisms of resistance.
摘要：
Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）是人类癌症中最常见的突变癌基因。在结直肠癌（CRC）中，KRAS突变存在于50%以上的病例中，和KRAS甘氨酸-半胱氨酸突变在密码子12（KRASG12C）发生在高达4％的患者。与非G12C突变相比,该突变与对标准化疗的短反应和更差的总体存活相关。近年来,几种KRASG12C抑制剂已经证明了临床活性，尽管所有患者最终进展。通过EGFR受体的负反馈的识别导致了KRAS抑制剂和抗EGFR组合的发展。从而增强抗肿瘤活性。目前,几种KRASG12C抑制剂正在开发中，I期和II期临床试验的结果是有希望的。此外，III期CodeBreaK300试验证明了索托拉西布-帕尼单抗优于氟尿苷/替吡嘧啶，为有KRASG12C突变的结直肠癌患者建立新的治疗标准.其他组合，如阿达格拉西布-西妥昔单抗，divarasib-西妥昔单抗,或FOLFIRI-帕尼单抗-索托拉西也显示出有意义的缓解率，目前正在评估中。尽管如此，这些患者中的大多数最终都会复发。在此设置中，液体活检成为表征耐药机制的关键工具，主要由MAPK和PI3K通路的获得性基因组改变和酪氨酸激酶受体改变组成，但是基因融合，组织学变化,也描述了激酶的构象变化。在本文中,本文综述了KRASG12C抑制剂在结直肠癌中的研究进展以及耐药的主要机制。
