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


Authors: Pereira, P. M. R.; Mandleywala, K.; Monette, S.; Lumish, M.; Tully, K. M.; Panikar, S. S.; Cornejo, M.; Mauguen, A.; Ragupathi, A.; Keltee, N. C.; Mattar, M.; Janjigian, Y. Y.; Lewis, J. S.
Article Title: Caveolin-1 temporal modulation enhances antibody drug 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 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. © 2022, The Author(s).
Keywords: retrospective studies; genetics; prospective study; prospective studies; metabolism; epidermal growth factor receptor 2; protein; drug resistance; pathology; breast neoplasms; retrospective study; biomarker; breast tumor; receptor, erbb-2; tumor; trastuzumab; hydroxymethylglutaryl coenzyme a reductase inhibitor; stomach neoplasms; antibody; stomach tumor; heterogeneity; hydroxymethylglutaryl-coa reductase inhibitors; membrane; caveolin 1; cancer; humans; human; female
Journal Title: Nature Communications
Volume: 13
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2022-05-09
Start Page: 2526
Language: English
DOI: 10.1038/s41467-022-30142-9
PUBMED: 35534471
PROVIDER: scopus
PMCID: PMC9085816
DOI/URL:
Notes: Article -- Export Date: 1 June 2022 -- Source: Scopus
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
  1. Yelena Yuriy Janjigian
    399 Janjigian
  2. Sebastien Monette
    150 Monette
  3. Jason S Lewis
    460 Lewis
  4. Melissa Amy Lumish
    39 Lumish
  5. Audrey   Mauguen
    157 Mauguen
  6. Marissa   Mattar
    57 Mattar
  7. Kathryn Margaret Tully
    12 Tully