曲妥珠单抗
癌症
抗药性
药理学
化疗
癌症研究
内科学
医学
乳腺癌
肿瘤科
生物
微生物学
作者
Bishan Liang,Qijing Wu,Yawen Wang,Yulu Shi,Fei Sun,Qiong Huang,Guanjun Li,Haibo Liu,Shuyi Zhang,Xin Xu,Guangyu Yao,Jianjun Peng,Xiaohui Zhai,Han Wang,Yujing Tan,Wei Xing Zheng,Rui Zhou,Shao-wei Li,Jianhua Wu,Ming Yang,Wangjun Liao,Min Shi
出处
期刊:Cancer Letters
[Elsevier]
日期:2024-04-01
卷期号:587: 216702-216702
被引量:2
标识
DOI:10.1016/j.canlet.2024.216702
摘要
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.
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