Cdc42-driven endosomal cholesterol transport promotes collateral resistance in HER2-positive gastric cancer
Bishan Liang1, Qijing Wu1, Yawen Wang1
1Department of Oncology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China.
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.
Insights
Resistance to trastuzumab in HER2-positive gastric cancer causes collateral resistance to chemotherapy. Inhibiting Cdc42 may reverse this, offering new treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Trastuzumab resistance is a major challenge in HER2-positive gastric cancer (GC).
- The impact of trastuzumab resistance on susceptibility to other drugs is not well understood.
- Understanding drug interplay is crucial for effective treatment selection and patient survival.
Purpose of the Study:
- To map the drug susceptibility profile of trastuzumab-resistant HER2-positive GC.
- To elucidate the mechanisms driving collateral resistance.
- To identify potential therapeutic targets for overcoming resistance.
Main Methods:
- Utilized trastuzumab-resistant GC cell lines and patient tissue specimens.
- Developed a 13-gene scoring model to identify collateral resistance.
- Investigated the role of endosomal cholesterol transport and the Hedgehog-ABCB1 axis.
- Examined the function of Cdc42 in cholesterol transport and resistance.
- Tested the efficacy of Cdc42 inhibition using ZCL278 in vitro and in vivo.
Main Results:
- Trastuzumab resistance induces collateral resistance to chemotherapy in HER2-positive GC.
- A 13-gene model predicts poor prognosis and sensitivity to cholesterol-lowering drugs in resistant patients.
- Endosomal cholesterol transport via the NPC1-TβRI-Cdc42 complex enriches plasma membrane cholesterol, driving resistance.
- Inhibition of Cdc42 activation with ZCL278 reduces cholesterol and reverses collateral resistance.
Conclusions:
- Trastuzumab resistance in GC is mechanistically linked to chemotherapy resistance via cholesterol transport.
- Cdc42 is a key mediator of this collateral resistance.
- Targeting Cdc42 activation presents a promising therapeutic strategy for second-line treatment of trastuzumab-resistant HER2-positive GC.
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