Trastuzumab-Resistant HER2+ 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

HER2-targeted therapies, such as trastuzumab, have increased the survival rates of HER2+ breast cancer patients. However, despite these therapies, many tumors eventually develop resistance to these therapies. Our lab previously reported an unexpected sensitivity of HER2+ 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+ 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+ trastuzumab resistant 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-κB-regulated genes. In particular, silencing PARP-1 inhibited NF-κB activity and reduced p65 binding at the IL-8 promoter, which resulted in a decrease in IL-8 mRNA and protein expression. Our results provide insight in the potential mechanism by which PARPi induces cytotoxicity in HER2+ breast cancer cells and support the testing of PARPi in patients with HER2+ breast cancer resistant to trastuzumab.