Response of Breast Cancer Cells to PARP Inhibitors Is Independent of BRCA Status.

Man Yee Keung,Francesca Badar,Jaydutt V Vadgama,Yanyuan Wu

doi:10.3390/jcm9040940

Abstract

Poly (ADP-ribose) polymerase inhibitors (PARPi) have proven to be beneficial to patients with metastatic breast cancer with BRCA1/2 (BReast CAncer type 1 and type 2 genes) mutations. However, certain PARPi in pre-clinical studies have been shown to inhibit cell growth and promote the death of breast cancer cells lacking mutations in BRCA1/2. Here, we examined the inhibitory potency of 13 different PARPi in 12 breast cancer cell lines with and without BRCA-mutations using cell viability assays. The results showed that 5 of the 8 triple-negative breast cancer (TNBC) cell lines were susceptible to PARPi regardless of the BRCA-status. The estrogen receptor (ER) negative/ human epidermal growth factor receptor 2 (HER2) positive (ER-/HER2+) cells, SKBR3 and JIMT1, showed high sensitivity to Talazoparib. Especially JIMT1, which is known to be resistant to trastuzumab, was responsive to Talazoparib at 0.002 µM. Niraparib, Olaparib, and Rucaparib also demonstrated effective inhibitory potency in both advanced TNBC and ER-/HER2+ cells with and without BRCA-mutations. In contrast, a BRCA-mutant TNBC line, HCC1937, was less sensitive to Talazoparib, Niraparib, Rucaparib, and not responsive to Olaparib. Other PARPi such as UPF1069, NU1025, AZD2461, and PJ34HCl also showed potent inhibitory activity in specific breast cancer cells. Our data suggest that the benefit of PARPi therapy in breast cancer is beyond the BRCA-mutations, and equally effective on metastatic TNBC and ER-/HER2+ breast cancers.

Highlights

Breast cancer is one of the most common cancers worldwide, and the leading cause of death in women [1]
The in vitro effect of 13 Poly (ADP-ribose) polymerase inhibitors (PARPi): A-966492, AG14361, AZD2461, E7449, G007-LK, Niraparib, NU1025, NMS-P118, Olaparib, PJ34-HCl, Rucaparib, Talazoparib, and UPF 1069 was tested on the selected 12 established human breast cancer cell lines (Table 2). Among those PARPis, Niraparib, Olaparib, Rucaparib, and Talazoparib have been approved by the FDA for treating advanced ovarian, pancreatic, and breast cancers [34]
Olaparib and Talazoparib have been approved as monotherapy in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer with germline BRCA mutation [20,34]

Summary

Introduction

Breast cancer is one of the most common cancers worldwide, and the leading cause of death in women [1]. Therapeutic failure and distant metastasis have been significant challenges in the treatment of breast cancer as well as the leading cause of mortality in breast cancer patients. African Americans, especially younger African Americans, are more likely to have TNBC that contributes significantly to increased mortality and cancer health disparities [3,4]. Another aggressive type of breast cancer is human epidermal growth factor receptor 2 positive (HER2+) breast cancer. Until the discovery and application of trastuzumab for the treatment for HER2+ breast cancer, patients with HER2+ tumors had inferior disease outcomes [5,6]. Almost 52% of HER2+ patients will fail trastuzumab treatment, leading to disease progression [7]

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