Department of Medicine, University of Chicago, 5841 S Maryland Ave, Chicago, IL 60637. USA.
Section of Hematology/Oncology, Department of Medicine, University of Chicago, 5841 S Maryland Ave, Chicago, IL 60637. USA.
Curr Probl Cancer. 2024 Aug;51:101106. doi: 10.1016/j.currproblcancer.2024.101106. Epub 2024 Jun 15.
NSCLC has a diverse genomic background with mutations in key proto-oncogenic drivers including Kirsten rat sarcoma (KRAS) and epidermal growth factor receptor (EGFR). Roughly 40% of adenocarcinoma harbor Kras activating mutations regardless of smoking history. Most KRAS mutations are located at G12, which include G12C (roughly 40%), G12V (roughly 20%), and G12D (roughly 15%). KRAS mutated NSCLC have higher tumor mutational burden and some have increased PD-1 expression, which has resulted in better responses to immunotherapy than other oncogenes. While initial treatment for metastatic NSCLC still relies on chemo-immunotherapy, directly targeting KRAS has proven to be efficacious in treating patients with KRAS mutated metastatic NSCLC. To date, two G12C inhibitors have been FDA-approved, namely sotorasib and adagrasib. In this review, we summarize the different drug combinations used to target KRAS G12c, upcoming G12D inhibitors and novel therapies targeting KRAS.
非小细胞肺癌(NSCLC)具有多种基因组背景,包括关键原癌基因驱动突变,如 Kirsten 大鼠肉瘤(KRAS)和表皮生长因子受体(EGFR)。大约 40%的腺癌无论吸烟史如何都携带有 Kras 激活突变。大多数 KRAS 突变位于 G12,包括 G12C(约 40%)、G12V(约 20%)和 G12D(约 15%)。KRAS 突变型 NSCLC 具有更高的肿瘤突变负担,并且一些具有增加的 PD-1 表达,这导致对免疫疗法的反应优于其他致癌基因。虽然转移性 NSCLC 的初始治疗仍依赖于化疗免疫治疗,但直接靶向 KRAS 已被证明对治疗 KRAS 突变型转移性 NSCLC 患者有效。迄今为止,已有两种 G12C 抑制剂获得 FDA 批准,即 sotorasib 和 adagrasib。在这篇综述中,我们总结了用于靶向 KRAS G12c 的不同药物组合、即将推出的 G12D 抑制剂以及针对 KRAS 的新型疗法。
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