Shi Min, Yang Yingxi, Huang Na, Zeng Dongqiang, Mo Zongchao, Wang Jiao, Zhang Xiaomeng, Liu Ran, Wang Chunlin, Rong Xiaoxiang, Wu Zhenzhen, Huang Qiong, Shang Haixia, Tang Jihong, Wang Zhaojun, Cai Jianan, Huang Genjie, Guan Yijin, Guo Jian, Mu Quanhua, Wang Jiguang, Liao Wangjun
Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China; Cancer Center, the Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, China; Foshan Key Laboratory of Translational Medicine in Oncology, the Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, China.
Department of Chemical and Biological Engineering, Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China.
Cell Rep Med. 2024 Dec 17;5(12):101838. doi: 10.1016/j.xcrm.2024.101838. Epub 2024 Dec 3.
Drug resistance limits the efficacy of chemotherapy for colorectal cancer liver metastasis (CRLM). However, the evolution of CRLM during drug treatment remains poorly elucidated. Multi-omics and treatment response data from 115 samples of 49 patients with CRLM undergoing bevacizumab (BVZ)-based chemotherapy show little difference in genomic alterations in 92% of cases, while remarkable differences are observed at the transcriptomic level. By decoupling intrinsic and acquired resistance, we find that hepatocyte and myeloid cell infiltration contribute to 38.5% and 23.1% of acquired resistance, respectively. Importantly, SMAD4 mutations and chr20q copy-number gain are associated with intrinsic chemoresistance. Gene interference experiments suggest that SMAD4 mutations confer BVZ and 5-fluorouracil (5-FU) resistance through STAT3 signaling. Notably, supplementing BVZ and 5-FU with the STAT3 inhibitor GB201 restores therapeutic efficacy in SMAD4 cancer cells. Our study uncovers the evolutionary dynamics of CRLM and its microenvironment during treatment and offers strategies to overcome drug resistance.
耐药性限制了结直肠癌肝转移（CRLM）化疗的疗效。然而，CRLM在药物治疗期间的演变仍未得到充分阐明。来自49例接受基于贝伐单抗（BVZ）化疗的CRLM患者的115个样本的多组学和治疗反应数据显示，92%的病例在基因组改变方面差异不大，而在转录组水平观察到显著差异。通过区分内在耐药性和获得性耐药性，我们发现肝细胞和髓样细胞浸润分别占获得性耐药性的38.5%和23.1%。重要的是，SMAD4突变和20号染色体q臂拷贝数增加与内在化疗耐药性相关。基因干扰实验表明，SMAD4突变通过STAT3信号传导赋予BVZ和5-氟尿嘧啶（5-FU）耐药性。值得注意的是，用STAT3抑制剂GB201补充BVZ和5-FU可恢复SMAD4癌细胞的治疗效果。我们的研究揭示了CRLM及其微环境在治疗期间的进化动态，并提供了克服耐药性的策略。
