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Caveolin-1 temporal modulation enhances antibody drug efficacy in heterogeneous gastric cancer
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Caveolin-1 temporal modulation enhances antibody drug efficacy in heterogeneous gastric cancer
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Journal Article
Caveolin-1 temporal modulation enhances antibody drug efficacy in heterogeneous gastric cancer
2022
Overview
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.
Clinical evidences have demonstrated limited efficacy of HER2-targeted therapies in patients with gastric cancer (GC). Here the authors show that survival benefit to anti-HER2 antibody Trastuzumab is reduced in GC patients with high levels of the caveolin-1 and that, in preclinical cancer models, antibody drug efficacy can be improved by modulating caveolin-1 levels with cholesterol-depleting drugs, statins.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 14/1
/ 14/63
/ 59
/ 59/78
/ 64
/ 64/60
/ 82/1
/ 96
/ Biological models (mathematics)
/ Cancer
/ Caveolin
/ Drugs
/ Female
/ Humanities and Social Sciences
/ Humans
/ Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use
/ Patients
/ Proteins
/ Receptor, ErbB-2 - metabolism
/ Science
/ Statins
/ Stomach Neoplasms - drug therapy
/ Stomach Neoplasms - genetics
/ Stomach Neoplasms - pathology
/ Survival
/ Trastuzumab - therapeutic use
/ Tumors
