Extracellular matrix/integrin signaling promotes resistance to combined inhibition of HER2 and PI3K in HER2+ breast cancer

Ariella B. Hanker, Mónica Valeria Estrada, Giampaolo Bianchini, Preston D. Moore, Junfei Zhao, Feixiong Cheng, James P. Koch, Luca Gianni, Darren R. Tyson, Violeta Sanchez, Brent N. Rexer, Melinda E. Sánders, Zhongming Zhao, Thomas P. Stricker, Carlos L. Arteaga

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

PIK3CA mutations are associated with resistance to HER2-targeted therapies. We previously showed that HER2+/PIK3CAH1047R transgenic mammary tumors are resistant to the HER2 antibodies trastuzumab and pertuzumab but respond to PI3K inhibitor buparlisib (TPB). In this study, we identified mechanisms of resistance to combined inhibition of HER2 and PI3K. TPB-resistant tumors were generated by treating HER2+/PIK3CAH1047R tumor-bearing mice long term with the drug combination. RNA sequencing of TPB-resistant tumors revealed that extracellular matrix and cell adhesion genes, including collagen II (Col2a1), were markedly upregulated, accompanied by activation of integrin β1/Src. Cells derived from drug-resistant tumors were sensitive to TBP when grown in vitro, but exhibited resistance when plated on collagen or when reintroduced into mice. Drug resistance was partially reversed by the collagen synthesis inhibitor ethyl-3,4- dihydroxybenzoate. Inhibition of integrin β1/Src blocked collagen- induced resistance to TPB and inhibited growth of drugresistant tumors. High collagen II expression was associated with significantly lower clinical response to neoadjuvant anti-HER2 therapy in HER2+ breast cancer patients. Overall, these data suggest that upregulation of collagen/integrin/Src signaling contributes to resistance to combinatorial HER2 and PI3K inhibition.

Original languageEnglish (US)
Pages (from-to)3280-3292
Number of pages13
JournalCancer Research
Volume77
Issue number12
DOIs
StatePublished - Jun 15 2017

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Hanker, A. B., Estrada, M. V., Bianchini, G., Moore, P. D., Zhao, J., Cheng, F., Koch, J. P., Gianni, L., Tyson, D. R., Sanchez, V., Rexer, B. N., Sánders, M. E., Zhao, Z., Stricker, T. P., & Arteaga, C. L. (2017). Extracellular matrix/integrin signaling promotes resistance to combined inhibition of HER2 and PI3K in HER2+ breast cancer. Cancer Research, 77(12), 3280-3292. https://doi.org/10.1158/0008-5472.CAN-16-2808