Abstract 1230: Talazoparib, a second generation PARP inhibitor, is a novel therapy for PTEN mutants in prostate cancer
Authors: Reinstein Zachary Z. , Vatapalli Rajita , Anker Jonathan , Pamarthy Sahithi , Carneiro Benedito , Abdulkadir Sarki 
Published: July 2017

Abstract
Prostate cancer is the most common cancer among men, other than skin cancer, in the United States. When the cancer enters into the metastatic castration resistant stage (mCRPC), few treatment options are currently available and the disease is considered incurable. The purpose of this study is to investigate a new, targeted therapy against prostate cancers, including mCRPC. Talazoparib is a novel PARP inhibitor with up to 100-fold higher potency and PARP affinity when compared to PARP inhibitors such as olaparib, veliparib, and rucaparib. Current literature suggests that PTEN mutants have high sensitivity to talazoparib. PTEN is a tumor suppressor gene that is commonly lost in prostate cancers. A murine prostate cancer cell line, Myc-CaP, which has been modified to overexpress the oncogene Myc, was edited by the CRISPR-Cas9 system to knock out the PTEN gene. Myc-CaP and Myc-CaP PTEN KO cells were treated with olaparib, an FDA approved, first generation PARP inhibitor, and talazoparib. Talazoparib decreased cell viability significantly more in PTEN KO cells versus PTEN wild-type (WT) cells. No such trend was observed when these cells were treated with olaparib. In addition, IC50 values in prostate cancer cell lines with heterozygous or homozygous deletion of PTEN were up to 20 times lower with the talazoparib treatment when compared to olaparib. Not only does this indicate that talazoparib is much more potent than olaparib, but also preferentially impairs cell growth in PTEN mutants. PTEN’s signal transduction prevents the phosphorylation of AKT, which is necessary for cell proliferation. When cells were treated with an AKT inhibitor, MK2206, alone or in combination with talazoparib, pAKT protein levels decreased, but the greatest effect was seen when MK2206 was used in combination with a low dose of talazoparib in the Myc-Cap cell line with wt PTEN. Western blot analysis showed that PTEN was upregulated following talazoparib treatment. These results indicate synergy of talazoparib and MK2206 in reducing the phosphorylation of AKT in a dose-dependent manner. Talazoparib is by far the most potent PARP inhibitor developed to date. With talazoparib potentially acting on prostate cancer with PTEN mutations, talazoparib treatment may expand current PARP inhibitor treatment in advanced prostate cancers and thereby elicit a response in as many as 80% of patients. Thus, talazoparib has vast therapeutic potential in prostate cancer.
Citation Format: Zachary Z. Reinstein, Rajita Vatapalli, Jonathan Anker, Sahithi Pamarthy, Benedito Carneiro, Sarki Abdulkadir. Talazoparib, a second generation PARP inhibitor, is a novel therapy for PTEN mutants in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1230. doi:10.1158/1538-7445.AM2017-1230