PHLDB2 Mediates Cetuximab Resistance via Interacting With EGFR in Latent Metastasis of Colorectal Cancer

• DOI: 10.1016/j.jcmgh.2021.12.011
• Publication Date: 2021-12-22T02:21:19Z
• Authors: Maochao Luo; Zhao Huang; Xingyue Yang; Yan Chen; Jingwen Jiang; Lu Zhang; Li Zhou; Siyuan Qin; Ping Jin; Shuyue Fu; Liyuan Peng; Bowen Li; Yongting Fang; Wenchen Pu; Yanqiu Gong; Yu Liu; Zhixiang Ren; Qiu-Luo Liu; Cun Wang; Fangqiong Xiao; Du He; Hongying Zhang; Changlong Li; Heng Xu; Lunzhi Dai; Yong Peng; Zong-Gung Zhou; Canhua Huang; Hai-Ning Chen
• Keywords: Colorectal Cancer; 0301 basic medicine; China; EGFR; Cetuximab Resistance; Cetuximab; Membrane Proteins; Antineoplastic Agents; RC799-869; Diseases of the digestive system. Gastroenterology; 3. Good health; ErbB Receptors; Mice; 03 medical and health sciences; Latent Metastasis; Animals; PHLDB2; Carrier Proteins; Colorectal Neoplasms; Original Research

Latent metastasis of colorectal cancer (CRC) frequently develops months or years after primary surgery, followed by adjuvant therapies, and may progress rapidly even with targeted therapy administered, but the underlying mechanism remains unclear. Here, we aim to explore molecular basis for aggressive behavior latent in CRC. Transcriptional profiling pathway enrichment analysis paired metastatic tumor samples were performed. The mechanisms pleckstrin homology-like domain, family B, member 2 (PHLDB2) CRC investigated RNA immunoprecipitation assay, immunohistochemistry, mass spectrometry analysis, Duolink situ proximity ligation assay (Sigma-Aldrich, Shanghai, China). efficacy targeting PHLDB2 cetuximab treatment was elucidated cell lines mouse models. Based on transcriptional profile samples, identified as a potential regulator liver metastasis. A detailed mechanistic study showed that chemotherapeutic agent-induced oxidative stress promotes methyltransferase-like 14 (METTL14)-mediated N6-methyladenosine modification messenger RNA, facilitating its protein expression. Up-regulated stabilizes epidermal growth factor receptor (EGFR) nuclear translocation, which turn results EGFR signaling activation consequent resistance. Moreover, Arg1163 (R1163) is crucial interaction EGFR, R1163A mutation abrogates regulatory function signaling. plays role resistance proposed be target