Caveolin-1 temporal modulation enhances antibody drug efficacy in heterogeneous gastric cancer

Patrícia M. R. Pereira (), Komal Mandleywala, Sébastien Monette, Melissa Lumish, Kathryn M. Tully, Sandeep Surendra Panikar, Mike Cornejo, Audrey Mauguen, Ashwin Ragupathi, Nai C. Keltee, Marissa Mattar, Yelena Y. Janjigian and Jason S. Lewis ()
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Patrícia M. R. Pereira: Memorial Sloan Kettering Cancer Center
Komal Mandleywala: Memorial Sloan Kettering Cancer Center
Sébastien Monette: Weill Cornell Medicine, and The Rockefeller University
Melissa Lumish: Memorial Sloan Kettering Cancer Center
Kathryn M. Tully: Memorial Sloan Kettering Cancer Center
Sandeep Surendra Panikar: Mallinckrodt Institute of Radiology, Washington University School of Medicine
Mike Cornejo: Memorial Sloan Kettering Cancer Center
Audrey Mauguen: Memorial Sloan Kettering Cancer Center
Ashwin Ragupathi: Memorial Sloan Kettering Cancer Center
Nai C. Keltee: Mallinckrodt Institute of Radiology, Washington University School of Medicine
Marissa Mattar: Memorial Sloan Kettering Cancer Center
Yelena Y. Janjigian: Memorial Sloan Kettering Cancer Center
Jason S. Lewis: Memorial Sloan Kettering Cancer Center

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30142-9

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