TY - JOUR
T1 - Caveolin-1 temporal modulation enhances antibody drug efficacy in heterogeneous gastric cancer
AU - Pereira, Patrícia M.R.
AU - Mandleywala, Komal
AU - Monette, Sébastien
AU - Lumish, Melissa
AU - Tully, Kathryn M.
AU - Panikar, Sandeep Surendra
AU - Cornejo, Mike
AU - Mauguen, Audrey
AU - Ragupathi, Ashwin
AU - Keltee, Nai C.
AU - Mattar, Marissa
AU - Janjigian, Yelena Y.
AU - Lewis, Jason S.
N1 - Funding Information:
We acknowledge the MSK Small-Animal Imaging Core Facility, the Radiochemistry and Molecular Imaging Probe Core, the Biostatistics Core, the Anti-tumor Assessment Core and Molecular Cytology Core Facility and the Immune Monitoring Facility, which were supported by NIH grant P30 CA08748. This study was supported in part by the Geoffrey Beene Cancer Research Center of MSK, NIH NCI R35 CA232130, NIH R01 CA244233-01A1. We gratefully acknowledge Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research and The Center for Experimental Therapeutics of MSK. P.M.R. Pereira acknowledges the Tow Foundation Postdoctoral Fellowship from the MSK Center for Molecular Imaging and Nanotechnology, the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center of MSK, the American Cancer Society (IRG-21-133-64-03), and NIH (R01 CA244233-01A1). We gratefully acknowledge Dr. Ricardo D’Oliveira Albanus from Department of Computational Medicine & Bioinformatics, University of Michigan for assistance in RStudio analyses. We would also like to acknowledge Dr. Marco Russo and Daniel Zakheim from the Gene Editing & Screening Core at MSK to assist in the Tet-on system. We are grateful to Dr. Elisa De Stanchina and all the team at the Antitumor Assessment Core for helping with the PDX models. We thank Dr. Fiona Simpson and Dr. Joseph Sun insightful suggestions regarding the experiments with NK cells. We are also thankful to Dr. Monica Shooken and Dr. Luis Batista for letting us use the BioTek plate reader and the Odyssey Infrared Imaging System, respectively.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85129460332&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-30142-9
DO - 10.1038/s41467-022-30142-9
M3 - Article
C2 - 35534471
AN - SCOPUS:85129460332
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2526
ER -