结直肠癌（CRC）在世界范围内是第三大致命的癌症，表现出高度的异质性。 KRASG12D的突变活化在大约10-12％的CRC病例中发生，但KRASG12D突变的CRC对最近发现的KRASG12D抑制剂MRTX1133的易感性尚未完全定义。在这里，我们报告MRTX1133处理导致KRASG12D突变的CRC细胞可逆生长停滞，伴随部分RAS效应器信号的重新激活。通过药物锚定的合成致死筛选，我们发现表皮生长因子受体（EGFR）抑制与MRTX1133合成为致死的。在机械上，MRTX1133处理下调了EGFR的重要负调节剂ERBB受体反馈抑制剂1（ERRFI1）的表达，从而引起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亚型，但不包括癌基因K-RAS，介导了EGFR活化的下游信号，导致RAS效应器信号的反弹和MRTX1133的效力降低。使用临床上使用的抗体或酪氨酸激酶抑制剂阻断活化的EGFR抑制了EGFR /野生型RAS信号轴，增敏了MRTX1133单药疗法，并引起了KRASG12D突变的CRC器官样和细胞系来源的移植瘤的消退。总的来说，这项研究揭示了EGFR的反馈激活作为限制KRASG12D抑制剂效力的重要分子事件，并建立了一个由KRASG12D和EGFR抑制剂组成的潜在联合疗法，适用于KRASG12D突变的CRC患者。©2023年作者。

Colorectal cancer (CRC), which shows a high degree of heterogeneity, is the third most deadly cancer worldwide. Mutational activation of KRASG12D occurs in approximately 10-12% of CRC cases, but the susceptibility of KRASG12D-mutated CRC to the recently discovered KRASG12D inhibitor MRTX1133 has not been fully defined. Here, we report that MRTX1133 treatment caused reversible growth arrest in KRASG12D-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 KRASG12D-mutant CRC organoids and cell line-derived xenografts. Overall, this study uncovers feedback activation of EGFR as a prominent molecular event that restricts KRASG12D inhibitor efficacy and establishes a potential combination therapy consisting of KRASG12D and EGFR inhibitors for patients with KRASG12D-mutated CRC.© 2023. The Author(s).