Southern Medical University Affiliated Fengxian Hospital, The Third School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, 510515, China.
Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
Oncogene. 2023 May;42(20):1620-1633. doi: 10.1038/s41388-023-02676-9. Epub 2023 Apr 5.
Colorectal cancer (CRC), which shows a high degree of heterogeneity, is the third most deadly cancer worldwide. Mutational activation of KRAS occurs in approximately 10-12% of CRC cases, but the susceptibility of KRAS-mutated CRC to the recently discovered KRAS inhibitor MRTX1133 has not been fully defined. Here, we report that MRTX1133 treatment caused reversible growth arrest in KRAS-mutated CRC cells, accompanied by partial reactivation of RAS effector signaling. Through a drug-anchored synthetic lethality screen, we discovered that epidermal growth factor receptor (EGFR) inhibition was synthetic lethal with MRTX1133. Mechanistically, MRTX1133 treatment downregulated the expression of ERBB receptor feedback inhibitor 1 (ERRFI1), a crucial negative regulator of EGFR, thereby causing EGFR feedback activation. Notably, wild-type isoforms of RAS, including H-RAS and N-RAS, but not oncogenic K-RAS, mediated signaling downstream of activated EGFR, leading to RAS effector signaling rebound and reduced MRTX1133 efficacy. Blockade of activated EGFR with clinically used antibodies or kinase inhibitors suppressed the EGFR/wild-type RAS signaling axis, sensitized MRTX1133 monotherapy, and caused the regression of KRAS-mutant CRC organoids and cell line-derived xenografts. Overall, this study uncovers feedback activation of EGFR as a prominent molecular event that restricts KRAS inhibitor efficacy and establishes a potential combination therapy consisting of KRAS and EGFR inhibitors for patients with KRAS-mutated CRC.
结直肠癌（CRC）表现出高度的异质性，是全球第三大致命癌症。大约有 10-12%的 CRC 病例中会发生 KRAS 突变激活，但 KRAS 突变型 CRC 对最近发现的 KRAS 抑制剂 MRTX1133 的敏感性尚未完全确定。在这里，我们报告 MRTX1133 治疗导致 KRAS 突变型 CRC 细胞可逆性生长停滞，并伴有 RAS 效应子信号的部分重新激活。通过药物锚定的合成致死性筛选，我们发现表皮生长因子受体（EGFR）抑制与 MRTX1133 具有合成致死性。在机制上，MRTX1133 治疗下调了 ERBB 受体反馈抑制剂 1（ERRFI1）的表达，ERRFI1 是 EGFR 的关键负调控因子，从而导致 EGFR 反馈激活。值得注意的是，包括 H-RAS 和 N-RAS 在内的野生型 RAS 异构体，但不是致癌的 K-RAS，介导激活的 EGFR 下游信号，导致 RAS 效应子信号反弹，降低 MRTX1133 的疗效。用临床使用的抗体或激酶抑制剂阻断激活的 EGFR 可抑制 EGFR/野生型 RAS 信号轴，增强 MRTX1133 单药治疗效果，并导致 KRAS 突变型 CRC 类器官和细胞系衍生的异种移植物的消退。总的来说，这项研究揭示了 EGFR 的反馈激活是限制 KRAS 抑制剂疗效的一个突出分子事件，并为 KRAS 突变型 CRC 患者建立了一种包含 KRAS 和 EGFR 抑制剂的潜在联合治疗策略。
