Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P. R. China; Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, P. R. China.
Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, P. R. China.
Drug Resist Updat. 2022 Dec;65:100883. doi: 10.1016/j.drup.2022.100883. Epub 2022 Sep 29.
This study aimed to identify mechanisms of drug resistance to the combination of vemurafenib, irinotecan, and cetuximab (VIC) in BRAF metastatic colorectal cancer (mCRC).
Forty-one patients with BRAF mCRC from July 2018 and June 2020 were evaluated, with tissue and/or plasma samples collected. We profiled tissue and plasma samples using whole-exome sequencing and targeted sequencing of 425 cancer-relevant genes. Clinical cohort analysis from published studies was performed to consolidate our findings.
BRAF mutant in baseline plasma and its dynamics are significantly associated with VIC-related response, and concurrent RNF43 mutation significantly sensitises tumour to VIC treatment. VIC resistance frequently involves genes in PI3K, MAPK pathway, and several novel resistance mechanisms such as TGFBR2 and SMAD4 mutations, and copy-number gains in PTK2, MYC, and GATA6 have been identified. We also firstly describe acquired altered genes in DNA damaging repair pathway, occurring in 33 % of patients after VIC treatment, and particularly, patients with this pre-treatment resistance subclones developed inferior responses, along with higher tumour mutation burden both at baseline and progression plasma.
Analysis of ctDNA can provide novel insights into molecular resistance mechanisms to VIC in BRAF mCRC patients, allowing accurate guidance for clinicians in personalised treatment strategies.
本研究旨在鉴定 BRAF 转移性结直肠癌（mCRC）患者接受维莫非尼、伊立替康和西妥昔单抗（VIC）联合治疗时产生耐药的机制。
评估了 2018 年 7 月至 2020 年 6 月期间 41 例 BRAF mCRC 患者，采集了组织和/或血浆样本。我们使用全外显子组测序和 425 个癌症相关基因的靶向测序对组织和血浆样本进行了分析。还对已发表研究中的临床队列进行了分析，以整合我们的研究结果。
基线血浆中 BRAF 突变及其动态与 VIC 相关反应显著相关，同时存在 RNF43 突变可使肿瘤对 VIC 治疗更敏感。VIC 耐药常涉及 PI3K、MAPK 通路中的基因，以及 TGFBR2 和 SMAD4 突变等几种新的耐药机制，还鉴定出了 PTK2、MYC 和 GATA6 的拷贝数增加。我们还首次描述了 DNA 损伤修复途径中获得的改变基因，在 VIC 治疗后 33%的患者中发生，特别是具有这种治疗前耐药亚克隆的患者，其反应较差，基线和进展血浆中的肿瘤突变负担均较高。
ctDNA 分析可为 BRAF mCRC 患者接受 VIC 治疗时的分子耐药机制提供新的见解，使临床医生能够在个体化治疗策略中进行准确指导。
