Androgen Receptor Inhibitor Enhances the Antitumor Effect of PARP Inhibitor in Breast Cancer Cells by Modulating DNA Damage Response

Abstract

The androgen receptor (AR) is expressed in 60%-70% of breast cancers regardless of estrogen receptor status, and has been proposed as a therapeutic target in breast cancers that retain AR. In this study, the authors aimed to investigate a new treatment strategy using a novel AR inhibitor AZD3514 in breast cancer. AZD3514 alone had a minimal antiproliferative effect on most breast cancer cell lines irrespective of AR expression level, but it downregulated the expressions of DNA damage response (DDR) molecules, including ATM and chk2, which resulted in the accumulation of damaged DNA in some breast cancer cells. Furthermore, AZD3514 enhanced cellular sensitivity to a PARP inhibitor olaparib by blocking the DDR pathway in breast cancer cells. Furthermore, the downregulation of NKX3.1 expression in MDA-MB-468 cells by AZD3514 occurred in parallel with the suppression of ATM-chk2 axis activation, and the suppression of NKX3.1 by AZD3514 was found to result from AZD3514-induced TOPORS upregulation and a resultant increase in NKX3.1 degradation. The study shows posttranslational regulation of NKX3.1 via TOPORS upregulation by AZD3514-induced ATM inactivation-increased olaparib sensitivity in AR-positive and TOPORS-expressing breast cancer cells, and suggests the antitumor effect of AZD3514/olaparib cotreatment is caused by compromised DDR activity in breast cancer cell lines and in a xenograft model. These results provide a rationale for future clinical trials of olaparib/AR inhibitor combination treatment in breast cancer.

Estrogen Receptor Positive Breast Cancer with High Expression of Androgen Receptor has Less Cytolytic Activity and Worse Response to Neoadjuvant Chemotherapy but Better Survival

“…AR was demonstrated to protect prostate cancer cells from DNA damage in vitro [29,30]. AR was also shown to maintain production of DNA damage response molecules in some breast cancer cells and it prevents the accumulation of damaged DNA in vitro [31]. Recent investigations have demonstrated that high AR expression was significantly associated with worse local recurrence-free survival after radiation therapy, which is known to induce DNA damage, and AR can be as a mediator of radioresistance in triple negative breast cancer [32].…”

Multi-omics analysis of serial samples from metastatic TNBC patients on PARP inhibitor monotherapy provide insight into rational PARP inhibitor therapy combinations

“…Indeed, in this study, the patient in case 1 who had rapid progression was AR positive and likely represented a luminal androgen receptor (LAR) subtype of breast cancer, rather than the basal subtype that dominates TNBC. AR expression in breast cancer has been shown to limit effects of PARPi in preclinical models and may explain the indifference of the tumor in case 1 to PARP inhibition (Li et al, 2017, Min et al, 2018, Luo et al, 2016). Both the MEDIOLA and TOPACIO trials demonstrated activity of PARP and ICB in TNBC.…”

“…In conclusion, preclinical models have identified a number of potential PARPi combinations, some of which have been evaluated in early phase clinical trials (Fang et al, 2018, Fang et al, 2019, Ibrahim et al, 2012, Jiao et al, 2017, Juvekar et al, 2012, Konstantinopoulos et al, 2019, Labrie et al, 2019b, Li et al, 2017, Liu et al, 2013, Matulonis et al, 2017, Min et al, 2018, Shen et al, 2019, Sun et al, 2017, Sun et al, 2018, Vena et al, 2018, Wang et al, 2019, Yin et al, 2017). However, responses, while encouraging in a subset of patients, remain limited in depth and duration.…”

The Homeodomain Transcription Factor NKX3.1 Modulates Bladder Outlet Obstruction Induced Fibrosis in Mice

“…Nkx3.1 was initially found as an androgen regulated homeobox gene located mainly in the prostate, and was extensively studied as a tumor suppressor in prostate cancer (23,24). Multiple studies, however, have since linked it to other tissue types and downregulation to their associated malignancies including the breast, oral mucosa, and liver (25)(26)(27)(28). There is scarce literature describing Nkx3.1 expression specifically in the bladder.…”