西妥昔单抗联合 FOLFIRI/FOLFOX 是 RAS 野生型转移性结直肠癌 (mCRC) 患者的标准一线治疗方法。然而，一些患者在接受西妥昔单抗治疗后会出现肿瘤快速进展（原发性耐药）。我们之前的研究发现了一个基因突变 REV1 p.R704Q，它可能是西妥昔单抗原发性耐药的关键生物标志物。本研究旨在研究REV1 p.R704Q突变引起西妥昔单抗耐药的机制，揭示诱导西妥昔单抗耐药的新机制。对208例mCRC患者的Sanger测序和多因素临床预后分析显示，REV1 p.R704Q突变是RAS野生型mCRC患者西妥昔单抗治疗后肿瘤进展的独立危险因素（危险比=2.481，95%置信区间： 1.389-4.431，P = 0.002）。 REV1 p.R704Q 突变细胞系对西妥昔单抗的敏感性在体外 Cell Counting Kit-8 测定和体内皮下肿瘤模型中降低。在体外，我们观察到 REV1 突变蛋白的稳定性降低和加速降解导致 REV1 功能障碍，从而激活自噬并介导西妥昔单抗耐药性。这些发现表明 REV1 p.R704Q 突变可以预测 mCRC 中西妥昔单抗的原发耐药性。 REV1 p.R704Q突变导致REV1蛋白稳定性下降和降解，以及p.R704Q蛋白功能障碍。 REV1 p.R704Q突变激活自噬并介导西妥昔单抗耐药；此外，抑制自噬可以逆转西妥昔单抗耐药性。版权所有 © 2024。由 Elsevier B.V. 出版。

Cetuximab in combination with FOLFIRI/FOLFOX is the standard first-line treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC). However, some patients experience rapid tumor progression after treatment with cetuximab (primary resistance). Our previous research identified a gene mutation, REV1 p.R704Q, which may be a key biomarker for primary cetuximab resistance. This study aimed to study the mechanism of cetuximab resistance caused by REV1 p.R704Q mutation and reveal a novel mechanism to induce cetuximab resistance. Sanger sequencing and multivariate clinical prognostic analysis of 208 patients with mCRC showed that REV1 p.R704Q mutation is an independent risk factor for tumor progression after treatment with cetuximab in patients with RAS wild-type mCRC (Hazard ratio=2.481, 95% Confidence interval: 1.389-4.431, P = 0.002). The sensitivity of REV1 p.R704Q mutant cell lines to cetuximab decreased in vitro Cell Counting Kit-8 assay and in vivo subcutaneous tumor model. In vitro, we observed that decreased stability and accelerated degradation of REV1 mutant protein results in REV1 dysfunction, which activated autophagy and mediated cetuximab resistance. These findings suggested that REV1 p.R704Q mutation could predict cetuximab primary resistance in mCRC. REV1 p.R704Q mutation caused decreased stability and degradation of REV1 protein, as well as dysfunction of p.R704Q protein. REV1 p.R704Q mutation activates autophagy and mediates cetuximab resistance; further, inhibition of autophagy could reverse cetuximab resistance.Copyright © 2024. Published by Elsevier B.V.