Trastuzumab-Resistant HER2+ 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 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 and tumor growth of HER2 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-κB-regulated genes. In particular, silencing PARP-1 inhibited NF-κB 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 breast cancer cells and support the testing of PARPi in patients with HER2 breast cancer resistant to trastuzumab. .

Resistance to HER2-Targeted Therapies Results in Upregulation of MCL-1 and Sensitivity to Olaparib

“…Acquired resistance to lapatinib has been shown to be heterogeneous in nature and involves a myriad of pathways and can vary across cell lines [31,36]. Supporting our observations, veliparib, another PARP inhibitor, was reported to induce apoptosis in a three cell line models of trastuzumab resistance [45]. Our results provide evidence to support the continued research into the effects of single-agent PARPi or in combination with HER2 targeted therapies for the treatment of HER2 positive breast cancers with acquired resistance to HER2-targeted therapies.…”

PARP14 promotes the proliferation and gemcitabine chemoresistance of pancreatic cancer cells through activation of NF‐κB pathway

“…However, PARPs, as well as macro‐PARP family members, were closely related with NF‐κB signaling in human diseases. For instance, PARPi (PARP inhibitors) induced cytotoxicity in HER2 + breast cancer cells through inhibition of NF‐κB signaling and reduced p65 binding at the IL8 promoter . Kwon et al reported that the PARP inhibitors (olaparib) could overcome cisplatin resistance of head and neck cancer cells via PAR‐p53‐NF‐κB interactions.…”

“…For instance, PARPi (PARP inhibitors) induced cytotoxicity in HER2 + breast cancer cells through inhibition of NF-κB signaling and reduced p65 binding at the IL8 promoter. 26 Hunter et al 28 revealed that PARP-1 was differentially required in the induction of NF-κB, and radiosensitization by PARP-1 inhibition was exclusively due to the inhibition of NF-κB. PARP10, also a member of mono-ADP ribosyltransferase, repressed the activation of NF-κB signaling and downstream target proteins based on catalytic activity and polyubiquitin binding of PARP10.…”

CHK1/2 Inhibitor Prexasertib Suppresses NOTCH Signaling and Enhances Cytotoxicity of Cisplatin and Radiation in Head and Neck Squamous Cell Carcinoma

“…19). Samples were processed for analysis using the PanCancer Pathways Plus panel as per the manufacturer's (7,17). The nSolver 4.0 program was used in data analysis.…”