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

doi:10.1158/0008-5472.CAN-16-2808

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

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66 Scopus citations

Abstract

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 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 language	English (US)
Pages (from-to)	3280-3292
Number of pages	13
Journal	Cancer research
Volume	77
Issue number	12
DOIs	https://doi.org/10.1158/0008-5472.CAN-16-2808
State	Published - Jun 15 2017

ASJC Scopus subject areas

Oncology
Cancer Research

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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

Hanker, AB, Estrada, MV, Bianchini, G, Moore, PD, Zhao, J, Cheng, F, Koch, JP, Gianni, L, Tyson, DR, Sanchez, V, Rexer, BN, Sánders, ME, Zhao, Z, Stricker, TP & Arteaga, CL 2017, 'Extracellular matrix/integrin signaling promotes resistance to combined inhibition of HER2 and PI3K in HER2⁺ breast cancer', Cancer research, vol. 77, no. 12, pp. 3280-3292. https://doi.org/10.1158/0008-5472.CAN-16-2808

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

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.",

author = "Hanker, {Ariella B.} and Estrada, {M{\'o}nica Valeria} and Giampaolo Bianchini and Moore, {Preston D.} and Junfei Zhao and Feixiong Cheng and Koch, {James P.} and Luca Gianni and Tyson, {Darren R.} and Violeta Sanchez and Rexer, {Brent N.} and S{\'a}nders, {Melinda E.} and Zhongming Zhao and Stricker, {Thomas P.} and Arteaga, {Carlos L.}",

note = "Publisher Copyright: {\textcopyright} 2017 American Association for Cancer Research.",

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doi = "10.1158/0008-5472.CAN-16-2808",

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T1 - Extracellular matrix/integrin signaling promotes resistance to combined inhibition of HER2 and PI3K in HER2+ breast cancer

AU - Hanker, Ariella B.

AU - Estrada, Mónica Valeria

AU - Bianchini, Giampaolo

AU - Moore, Preston D.

AU - Zhao, Junfei

AU - Cheng, Feixiong

AU - Koch, James P.

AU - Gianni, Luca

AU - Tyson, Darren R.

AU - Sanchez, Violeta

AU - Rexer, Brent N.

AU - Sánders, Melinda E.

AU - Zhao, Zhongming

AU - Stricker, Thomas P.

AU - Arteaga, Carlos L.

PY - 2017/6/15

Y1 - 2017/6/15

N2 - 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.

AB - 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.

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

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