Caveolin-1 temporal modulation enhances antibody drug efficacy in heterogeneous gastric cancer
Patrícia M R Pereira1,2, Komal Mandleywala3, Sébastien Monette4
1Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. ribeiropereirap@wustl.edu.
Abstract:
Resistance mechanisms and heterogeneity in HER2-positive gastric cancers (GC) limit Trastuzumab benefit in 32% of patients, and other targeted therapies have failed in clinical trials. Using patient samples, patient-derived xenografts (PDXs), partially humanized biological models, and HER2-targeted imaging technologies we demonstrate the role of caveolin-1 (CAV1) as a complementary biomarker in GC selection for Trastuzumab therapy. In retrospective analyses of samples from patients enrolled on Trastuzumab trials, the CAV1-high profile associates with low membrane HER2 density and low patient survival. We show a negative correlation between CAV1 tumoral protein levels - a major protein of cholesterol-rich membrane domains - and Trastuzumab-drug conjugate TDM1 tumor uptake. Finally, CAV1 depletion using knockdown or pharmacologic approaches (statins) increases antibody drug efficacy in tumors with incomplete HER2 membranous reactivity. In support of these findings, background statin use in patients associates with enhanced antibody efficacy. Together, this work provides preclinical justification and clinical evidence that require prospective investigation of antibody drugs combined with statins to delay drug resistance in tumors.
Insights
Caveolin-1 (CAV1) is a biomarker for HER2-positive gastric cancer (GC) treatment. High CAV1 levels correlate with poor survival and reduced Trastuzumab efficacy, suggesting statins may improve outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- HER2-positive gastric cancer (GC) exhibits resistance to Trastuzumab, limiting its effectiveness in a significant patient subset.
- Existing targeted therapies have shown limited success in clinical trials for GC.
- Heterogeneity in resistance mechanisms contributes to suboptimal outcomes in GC patients.
Purpose of the Study:
- To identify complementary biomarkers for selecting GC patients for Trastuzumab therapy.
- To investigate the role of caveolin-1 (CAV1) in mediating resistance to HER2-targeted therapies in GC.
- To explore therapeutic strategies combining HER2-targeted agents with agents targeting CAV1.
Main Methods:
- Analysis of patient samples from Trastuzumab trials.
- Utilized patient-derived xenografts (PDXs) and partially humanized biological models.
- Employed HER2-targeted imaging technologies and CAV1 depletion strategies (knockdown, statins).
Main Results:
- A high CAV1 profile in GC patients correlated with low membrane HER2 density and reduced survival.
- Elevated tumoral CAV1 protein levels negatively impacted Trastuzumab-drug conjugate (TDM1) uptake.
- CAV1 depletion, via knockdown or statins, enhanced antibody drug efficacy in tumors with incomplete HER2 reactivity.
- Background statin use in patients was associated with improved antibody efficacy.
Conclusions:
- Caveolin-1 (CAV1) serves as a complementary biomarker for Trastuzumab therapy selection in HER2-positive GC.
- Targeting CAV1, potentially with statins, can overcome resistance mechanisms and enhance antibody drug efficacy.
- Further prospective investigation of combining antibody drugs with statins is warranted to delay drug resistance in GC.
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