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Title: Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors

Abstract

Stiffness is a biophysical property of the extracellular matrix that modulates cellular functions, including proliferation, invasion, and differentiation, and it also may affect therapeutic responses. Therapeutic durability in cancer treatments remains a problem for both chemotherapies and pathway-targeted drugs, but the reasons for this are not well understood. Tumor progression is accompanied by changes in the biophysical properties of the tissue, and we asked whether matrix rigidity modulated the sensitive versus resistant states in HER2-amplified breast cancer cell responses to the HER2-targeted kinase inhibitor lapatinib. The antiproliferative effect of lapatinib was inversely proportional to the elastic modulus of the adhesive substrata. Down-regulation of the mechanosensitive transcription coactivators YAP and TAZ, either by siRNA or with the small-molecule YAP/TEAD inhibitor verteporfin, eliminated modulus-dependent lapatinib resistance. Reduction of YAP in vivo in mice also slowed the growth of implanted HER2-amplified tumors, showing a trend of increasing sensitivity to lapatinib as YAP decreased. Thus we address the role of stiffness in resistance to and efficacy of a HER2 pathway–targeted therapeutic via the mechanotransduction arm of the Hippo pathway.

Authors:
 [1];  [2];  [3];  [4];  [4];  [3];  [5]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division; Univ. of California, Berkeley, CA (United States). Program in Comparative Biochemistry
  2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division; Bergen Univ. (Norway). Dept. of Biomedicine
  3. Univ. of California, San Francisco, CA (United States).Dept. of Radiation Oncology
  4. Univ. of California, San Francisco, CA (United States). Dept. of Surgery. Center for Bioengineering, Tissue Regeneration
  5. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE; National Inst. of Health (NIH) (United States); Anita Tarr Turk Fund for Breast Cancer Research (United States)
Contributing Org.:
Univ. of California, Berkeley, CA (United States); Bergen Univ. (Norway)
OSTI Identifier:
1378635
Grant/Contract Number:  
AC02-05CH11231; R00AG033176; R01AG040081; 20IB-0109
Resource Type:
Accepted Manuscript
Journal Name:
Molecular Biology of the Cell
Additional Journal Information:
Journal Volume: 26; Journal Issue: 22; Journal ID: ISSN 1059-1524
Publisher:
American Society for Cell Biology
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Lin, Chun-Han, Pelissier, Fanny A., Zhang, Hui, Lakins, Jon, Weaver, Valerie M., Park, Catherine, and LaBarge, Mark A.. Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors. United States: N. p., 2015. Web. https://doi.org/10.1091/mbc.E15-07-0456.
Lin, Chun-Han, Pelissier, Fanny A., Zhang, Hui, Lakins, Jon, Weaver, Valerie M., Park, Catherine, & LaBarge, Mark A.. Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors. United States. https://doi.org/10.1091/mbc.E15-07-0456
Lin, Chun-Han, Pelissier, Fanny A., Zhang, Hui, Lakins, Jon, Weaver, Valerie M., Park, Catherine, and LaBarge, Mark A.. Wed . "Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors". United States. https://doi.org/10.1091/mbc.E15-07-0456. https://www.osti.gov/servlets/purl/1378635.
@article{osti_1378635,
title = {Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors},
author = {Lin, Chun-Han and Pelissier, Fanny A. and Zhang, Hui and Lakins, Jon and Weaver, Valerie M. and Park, Catherine and LaBarge, Mark A.},
abstractNote = {Stiffness is a biophysical property of the extracellular matrix that modulates cellular functions, including proliferation, invasion, and differentiation, and it also may affect therapeutic responses. Therapeutic durability in cancer treatments remains a problem for both chemotherapies and pathway-targeted drugs, but the reasons for this are not well understood. Tumor progression is accompanied by changes in the biophysical properties of the tissue, and we asked whether matrix rigidity modulated the sensitive versus resistant states in HER2-amplified breast cancer cell responses to the HER2-targeted kinase inhibitor lapatinib. The antiproliferative effect of lapatinib was inversely proportional to the elastic modulus of the adhesive substrata. Down-regulation of the mechanosensitive transcription coactivators YAP and TAZ, either by siRNA or with the small-molecule YAP/TEAD inhibitor verteporfin, eliminated modulus-dependent lapatinib resistance. Reduction of YAP in vivo in mice also slowed the growth of implanted HER2-amplified tumors, showing a trend of increasing sensitivity to lapatinib as YAP decreased. Thus we address the role of stiffness in resistance to and efficacy of a HER2 pathway–targeted therapeutic via the mechanotransduction arm of the Hippo pathway.},
doi = {10.1091/mbc.E15-07-0456},
journal = {Molecular Biology of the Cell},
number = 22,
volume = 26,
place = {United States},
year = {2015},
month = {9}
}

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