Trastuzumab-resistant HER2                         þ                          breast cancer cells retain sensitivity to poly (adp-ribose) polymerase (parp) inhibition

Monica E. Wielgos; Zhuo Zhang; Rajani Rajbhandari; Tiffiny S. Cooper; Ling Zeng; Andres Forero; Francisco J. Esteva; C. Kent Osborne; Rachel Schiff; Albert F. LoBuglio; Susan E. Nozell; Eddy S. Yang

doi:10.1158/1535-7163.MCT-17-0302

Trastuzumab-resistant HER2 ^þ breast cancer cells retain sensitivity to poly (adp-ribose) polymerase (parp) inhibition

Monica E. Wielgos, Zhuo Zhang, Rajani Rajbhandari, Tiffiny S. Cooper, Ling Zeng, Andres Forero, Francisco J. Esteva, C. Kent Osborne, Rachel Schiff, Albert F. LoBuglio, Susan E. Nozell, Eddy S. Yang

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

HER2-targeted therapies, such as trastuzumab, have increased the survival rates of HER2 ^þ breast cancer patients. However, despite these therapies, many tumors eventually develop resistance to these therapies. Our lab previously reported an unexpected sensitivity of HER2 ^þ breast cancer cells to poly (ADP-ribose) polymerase inhibitors (PARPi), agents that target homologous recombination (HR)–deficient tumors, independent of a DNA repair deficiency. In this study, we investigated whether HER2 ^þ trastuzumab-resistant (TR) breast cancer cells were susceptible to PARPi and the mechanism behind PARPi induced cytotoxicity. We demonstrate that the PARPi ABT-888 (veliparib) decreased cell survival in vitro and tumor growth in vivo of HER2 ^þ TR breast cancer cells. PARP-1 siRNA confirmed that cytotoxicity was due, in part, to PARP-1 inhibition. Furthermore, PARP-1 silencing had variable effects on the expression of several NF-kB–regulated genes. In particular, silencing PARP-1 inhibited NF-kB activity and reduced p65 binding at the IL8 promoter, which resulted in a decrease in IL8 mRNA and protein expression. Our results provide insight in the potential mechanism by which PARPi induces cytotoxicity in HER2 ^þ breast cancer cells and support the testing of PARPi in patients with HER2 ^þ breast cancer resistant to trastuzumab.

Original language	English
Pages (from-to)	921-930
Number of pages	10
Journal	Molecular Cancer Therapeutics
Volume	17
Issue number	5
DOIs	https://doi.org/10.1158/1535-7163.MCT-17-0302
State	Published - May 2018

Bibliographical note

Publisher Copyright:
© 2018 American Association for Cancer Research.

Funding

F.J. Esteva is a consultant/advisory board member for Genentech. C.K. Osborne is a consultant/advisory board member for AstraZeneca, Genentech, P. Elmer, and Pfizer, has received expert testimony from O'Melveny and Myers. R. Schiff reports receiving a commercial research grant from AstraZeneca. No potential conflicts of interest were disclosed by the other authors. We would like to thank Vivo Biosciences for their help with the microtumor experiments as well as Enid F. Keyser for her assistance with the apoptosis and cell cycle experiments. The authors would also like to thank Alice Weaver for her help with an experiment. This study was supported by grants from the American Association of Cancer Research/Genentech Career Development Award (12-30-18-YANG) to E.S. Yang), Susan G. Komen Career Catalyst Award (CCR12364491, to E.S. Yang), Breast Cancer Research Foundation of Alabama (to E.S. Yang), and the Breast SPORE (5P50CA089019 to E.S. Yang) from the University of Alabama-Birmingham Comprehensive Cancer Center. The UAB Comprehensive Flow Cytometry Core Facility is supported by Grants P30 AR048311 and Grant P30 AI027767. We would like to thank Vivo Biosciences for their help with the microtumor experiments as well as Enid F. Keyser for her assistance with the apoptosis and cell cycle experiments. The authors would also like to thank Alice Weaver for her help with an experiment. This study was supported by grants from the American Association of Cancer Research/Genentech Career Development Award (12-30-18-YANG) to E.S. Yang), Susan G. Komen Career Catalyst Award (CCR12364491, to E.S. Yang), Breast Cancer Research Foundation of Alabama (to E.S. Yang), and the Breast SPORE (5P50CA089019 to E.S. Yang) from the University of Alabama-Birmingham Comprehensive Cancer Center. The UAB

Funders	Funder number
American Association of Cancer Research/Genentech	12-30-18-YANG
Breast Cancer Research Foundation of Alabama	5P50CA089019
Department of Radiation Oncology, University of Alabama-Birmingham Comprehensive Cancer Center
American Association for Cancer Research
National Childhood Cancer Registry – National Cancer Institute	P50CA089019
National Childhood Cancer Registry – National Cancer Institute
AstraZeneca
Susan G Komen Foundation	CCR12364491
Susan G Komen Foundation

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1158/1535-7163.MCT-17-0302

Cite this

Wielgos, M. E., Zhang, Z., Rajbhandari, R., Cooper, T. S., Zeng, L., Forero, A., Esteva, F. J., Kent Osborne, C., Schiff, R., LoBuglio, A. F., Nozell, S. E., & Yang, E. S. (2018). Trastuzumab-resistant HER2 ^þ breast cancer cells retain sensitivity to poly (adp-ribose) polymerase (parp) inhibition Molecular Cancer Therapeutics, 17(5), 921-930. https://doi.org/10.1158/1535-7163.MCT-17-0302

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title = " Trastuzumab-resistant HER2 {\th} breast cancer cells retain sensitivity to poly (adp-ribose) polymerase (parp) inhibition ",

abstract = " HER2-targeted therapies, such as trastuzumab, have increased the survival rates of HER2 {\th} breast cancer patients. However, despite these therapies, many tumors eventually develop resistance to these therapies. Our lab previously reported an unexpected sensitivity of HER2 {\th} breast cancer cells to poly (ADP-ribose) polymerase inhibitors (PARPi), agents that target homologous recombination (HR)–deficient tumors, independent of a DNA repair deficiency. In this study, we investigated whether HER2 {\th} trastuzumab-resistant (TR) breast cancer cells were susceptible to PARPi and the mechanism behind PARPi induced cytotoxicity. We demonstrate that the PARPi ABT-888 (veliparib) decreased cell survival in vitro and tumor growth in vivo of HER2 {\th} TR breast cancer cells. PARP-1 siRNA confirmed that cytotoxicity was due, in part, to PARP-1 inhibition. Furthermore, PARP-1 silencing had variable effects on the expression of several NF-kB–regulated genes. In particular, silencing PARP-1 inhibited NF-kB activity and reduced p65 binding at the IL8 promoter, which resulted in a decrease in IL8 mRNA and protein expression. Our results provide insight in the potential mechanism by which PARPi induces cytotoxicity in HER2 {\th} breast cancer cells and support the testing of PARPi in patients with HER2 {\th} breast cancer resistant to trastuzumab.",

author = "Wielgos, {Monica E.} and Zhuo Zhang and Rajani Rajbhandari and Cooper, {Tiffiny S.} and Ling Zeng and Andres Forero and Esteva, {Francisco J.} and {Kent Osborne}, C. and Rachel Schiff and LoBuglio, {Albert F.} and Nozell, {Susan E.} and Yang, {Eddy S.}",

note = "Publisher Copyright: {\textcopyright} 2018 American Association for Cancer Research.",

year = "2018",

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Wielgos, ME, Zhang, Z, Rajbhandari, R, Cooper, TS, Zeng, L, Forero, A, Esteva, FJ, Kent Osborne, C, Schiff, R, LoBuglio, AF, Nozell, SE & Yang, ES 2018, ' Trastuzumab-resistant HER2 ^þ breast cancer cells retain sensitivity to poly (adp-ribose) polymerase (parp) inhibition ', Molecular Cancer Therapeutics, vol. 17, no. 5, pp. 921-930. https://doi.org/10.1158/1535-7163.MCT-17-0302

Trastuzumab-resistant HER2 ^þ breast cancer cells retain sensitivity to poly (adp-ribose) polymerase (parp) inhibition . / Wielgos, Monica E.; Zhang, Zhuo; Rajbhandari, Rajani et al.
In: Molecular Cancer Therapeutics, Vol. 17, No. 5, 05.2018, p. 921-930.

Research output: Contribution to journal › Article › peer-review

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AU - Cooper, Tiffiny S.

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Wielgos ME, Zhang Z, Rajbhandari R, Cooper TS, Zeng L, Forero A et al. Trastuzumab-resistant HER2 ^þ breast cancer cells retain sensitivity to poly (adp-ribose) polymerase (parp) inhibition Molecular Cancer Therapeutics. 2018 May;17(5):921-930. doi: 10.1158/1535-7163.MCT-17-0302