Caveolin-1 temporal modulation enhances trastuzumab and trastuzumab-drug conjugate efficacy in heterogeneous gastric cancer
Caveolin-1 temporal modulation enhances trastuzumab and trastuzumab-drug conjugate efficacy in heterogeneous gastric cancer
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 genomic data from patient tissue, patient-derived xenografts (PDXs), partially humanized biological models, and HER2-targeted imaging we identified 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 was associated with low membrane HER2 density and reduced patient survival. We found 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 was shown to increase HER2-directed immunoPET uptake and TDM1 efficacy in GC with incomplete HER2 membranous reactivity. In support of these findings, background statin use in patients is associated with enhanced antibody efficacy. Together, this work provides mechanistic justification and clinical evidence that require prospective investigation of HER2-targeted therapies combined with statins to delay drug resistance in GC. SIGNIFICANCEThis study identifies how CAV1 protein expression and statin use relate to GC response in HER2-targeted imaging and therapeutic approaches. In addition, to support the synergy of CAV1 depletion with TDM1 observed in mouse models, we demonstrate that statin users had better clinical responses to antibody-based therapies in HER2+ GC.
Mauguen Audrey、Mattar Marissa、Mandleywala Komal、Lumish Melissa、Monette S¨|bastien、Lewis Jason S.、Janjigian Yelena Y.、Ragupathi Ashwin、Tully Kathryn M.、Pereira Patr¨acia M. R.、Cornejo Mike
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer CenterAntitumor Assessment Core Facility, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer CenterDepartment of Radiology, Memorial Sloan Kettering Cancer CenterDepartment of Medicine, Memorial Sloan Kettering Cancer CenterLaboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, and The Rockefeller UniversityDepartment of Radiology, Memorial Sloan Kettering Cancer Center||Department of Pharmacology, Weill Cornell Medical College||Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center||Department of Radiology, Weill Cornell Medical College||Radiochemistry and Molecular Imaging Probes Core, Memorial Sloan Kettering Cancer CenterDepartment of Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Radiology, Memorial Sloan Kettering Cancer CenterDepartment of Radiology, Memorial Sloan Kettering Cancer Center||Department of Pharmacology, Weill Cornell Medical CollegeDepartment of Radiology, Memorial Sloan Kettering Cancer CenterDepartment of Radiology, Memorial Sloan Kettering Cancer Center
肿瘤学基础医学药学
gastric cancerHER2membrane availabilitystatins
Mauguen Audrey,Mattar Marissa,Mandleywala Komal,Lumish Melissa,Monette S¨|bastien,Lewis Jason S.,Janjigian Yelena Y.,Ragupathi Ashwin,Tully Kathryn M.,Pereira Patr¨acia M. R.,Cornejo Mike.Caveolin-1 temporal modulation enhances trastuzumab and trastuzumab-drug conjugate efficacy in heterogeneous gastric cancer[EB/OL].(2025-03-28)[2025-08-14].https://www.biorxiv.org/content/10.1101/2021.07.13.452260.点此复制
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