Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors.
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.
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720 Program in Comparative Biochemistry, University of California, Berkeley, Berkeley, CA 94720.
Chun-Han
CH
Lin
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720 Department of Biomedicine, University of Bergen, N-5009 Bergen, Norway.
Fanny A
FA
Pelissier
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA 94143.
Hui
H
Zhang
Center for Bioengineering, Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143.
Jon
J
Lakins
Center for Bioengineering, Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143.
Valerie M
VM
Weaver
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA 94143.
Catherine
C
Park
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720 malabarge@lbl.gov.
Mark A
MA
LaBarge
D000217:Acyltransferases; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011166:Porphyrins / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D059016:Tumor Microenvironment; D000077362:Verteporfin; D023041:Xenograft Model Antitumor Assays
D000217:Acyltransferases; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D000077341:Lapatinib; D009687:Nuclear Proteins; D011166:Porphyrins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; D000077362:Verteporfin; C456659:YY1AP1 protein, human; C108675:TAFAZZIN protein, human; C508053:ERBB2 protein, human