Extracellular Matrix/Integrin Signaling Promotes Resistance to Combined Inhibition of HER2 and PI3K in HER2 Breast Cancer

Overview

Journal Cancer Res

Specialty Oncology

Date 2017 Apr 12

PMID 28396358

Citations 58

Authors

Ariella B Hanker

Monica 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 Sanders

Zhongming Zhao

Thomas P Stricker

Carlos L Arteaga

Affiliations

Soon will be listed here.

Abstract

mutations are associated with resistance to HER2-targeted therapies. We previously showed that 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 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 (), were markedly upregulated, accompanied by activation of integrin β1/Src. Cells derived from drug-resistant tumors were sensitive to TBP when grown , 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 drug-resistant 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. .

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