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

被引：78

作者：

Hanker, Ariella B. ^{[1
,2
]}

Estrada, Monica Valeria ^{[2
]}

Bianchini, Giampaolo ^{[3
]}

Moore, Preston D. ^{[1
]}

Zhao, Junfei ^{[4
]}

Cheng, Feixiong ^{[4
]}

Koch, James P. ^{[1
]}

Gianni, Luca ^{[3
]}

Tyson, Darren R. ^{[5
]}

Sanchez, Violeta ^{[2
]}

Rexer, Brent N. ^{[1
]}

Sanders, Melinda E. ^{[2
,6
]}

Zhao, Zhongming ^{[4
,7
]}

Stricker, Thomas P. ^{[2
,6
]}

Arteaga, Carlos L. ^{[1
,2
,5
]}

机构：

[1] Vanderbilt Univ, Med Ctr, Dept Med, Vanderbilt Ingram Canc Ctr, Nashville, TN USA

[2] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Breast Canc Program, Nashville, TN USA

[3] IRCCS Osped San Raffaele, Dept Med Oncol, Milan, Italy

[4] Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Vanderbilt Ingram Canc Ctr, Nashville, TN USA

[5] Vanderbilt Univ, Med Ctr, Dept Canc Biol, Vanderbilt Ingram Canc Ctr, Nashville, TN USA

[6] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN USA

[7] Univ Texas Hlth Sci Ctr Houston, Sch Biomed Informat, Ctr Precis Hlth, Houston, TX 77030 USA

来源：

CANCER RESEARCH | 2017年 / 77卷 / 12期

关键词：

PATHOLOGICAL COMPLETE RESPONSE; PIK3CA MUTATIONS; MAMMARY-TUMORS; OPEN-LABEL; TRASTUZUMAB; PERTUZUMAB; LAPATINIB; GROWTH; CELLS; BETA-1-INTEGRIN;

D O I：

10.1158/0008-5472.CAN-16-2808

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

PIK3CA mutations are associated with resistance to HER2-targeted therapies. We previously showed that HER2(+)/PIK3CA(H1047R) 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(+)/PIK3CA(H1047R) 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 beta 1/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 beta 1/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. (C) 2017 AACR.

引用

页码：3280 / 3292

页数：13

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