2. Academic Validation
  3. Cdc42-driven endosomal cholesterol transport promotes collateral resistance in HER2-positive gastric cancer

Cdc42-driven endosomal cholesterol transport promotes collateral resistance in HER2-positive gastric cancer

  • Cancer Lett. 2024 Apr 10:587:216702. doi: 10.1016/j.canlet.2024.216702.
Bishan Liang 1,  Qijing Wu 1,  Yawen Wang 1,  Yulu Shi 1,  Fei Sun 1,  Qiong Huang 1,  Guanjun Li 1,  Yajing Liu 2,  Shuyi Zhang 3,  Xin Xu 1,  Guangyu Yao 4,  Jianjun Peng 5,  Xiaohui Zhai 6,  Jing Wu 7,  Yujing Tan 8,  Zhenzhen Wu 1,  Rui Zhou 1,  Shaowei Li 1,  Jianhua Wu 1,  Ming Yang 9,  Wangjun Liao 1,  Min Shi 10
Affiliations

Affiliations

  • 1 Department of Oncology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China.
  • 2 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Medical Oncology, Breast Tumor Center, Phase I Clinical Trial Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510060, Guangzhou, China.
  • 3 Department of Oncology, Huizhou Municipal Central Hospital, 516008, Huizhou, Guangdong, China.
  • 4 Department of General Surgery, Breast Center, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China.
  • 5 Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, 510060, Guangzhou, Guangdong, China.
  • 6 Department of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-sen University, 510655, Guangzhou, Guangdong, China.
  • 7 Department of Oncology, The People's Hospital of Foshan, 528010, Foshan, Guangdong, China.
  • 8 Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, 510280, Guangzhou, Guangdong, China.
  • 9 Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, 271016, Jinan, Shandong, China.
  • 10 Department of Oncology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China. Electronic address: shimin@smu.edu.cn.
PMID: 38336288 DOI: 10.1016/j.canlet.2024.216702
Abstract

Resistance to trastuzumab and the poor efficacy of subsequent chemotherapy have become major challenges for HER2-positive gastric Cancer (GC). As resistance evolves, tumor cells may acquire a new drug susceptibility profile, profoundly impacting the subsequent treatment selection and patient survival. However, the interplay between trastuzumab and Other types of drugs in HER2-positive GC remains elusive. In our study, we utilized resistant cell lines and tissue specimens to map the drug susceptibility profile of trastuzumab-resistant GC, discovering that resistance to trastuzumab induces collateral resistance to commonly used chemotherapeutic agents. Additionally, patients with collateral resistance distinguished by a 13-gene scoring model in HER2-positive GC cohorts are predicted to have a poor prognosis and may be sensitive to cholesterol-lowering drugs. Mechanistically, endosomal Cholesterol transport is further confirmed to enrich Cholesterol in the plasma membrane, contributing to collateral resistance through the Hedgehog-ABCB1 axis. As a driver for Cholesterol, Cdc42 is activated by the formation of the NPC1-TβRI-Cdc42 complex to facilitate endosomal Cholesterol transport. We demonstrated that inhibiting Cdc42 activation with ZCL278 reduces Cholesterol levels in the plasma membrane and reverses collateral resistance between trastuzumab and chemotherapy in vitro and in vivo. Collectively, our findings verify the phenomena and mechanism of collateral resistance between trastuzumab and chemotherapy, and propose a potential therapeutic target and strategy in the second-line treatment for trastuzumab-resistant HER2-positive GC.

Keywords

Cdc42; Cholesterol reprogramming; Collateral resistance; Gastric cancer; Trastuzumab.

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