The PARP Inhibitor AZD2461 Provides Insights into the Role of PARP3 Inhibition for Both Synthetic Lethality and Tolerability with Chemotherapy in Preclinical Models

Abstract

The PARP inhibitor AZD2461 was developed as a next-generation agent following olaparib, the first PARP inhibitor approved for cancer therapy. In BRCA1-deficient mouse models, olaparib resistance predominantly involves overexpression of P-glycoprotein, so AZD2461 was developed as a poor substrate for drug transporters. Here we demonstrate the efficacy of this compound against olaparib-resistant tumors that overexpress P-glycoprotein. In addition, AZD2461 was better tolerated in combination with chemotherapy than olaparib in mice, which suggests that AZD2461 could have significant advantages over olaparib in the clinic. However, this superior toxicity profile did not extend to rats. Investigations of this difference revealed a differential PARP3 inhibitory activity for each compound and a higher level of PARP3 expression in bone marrow cells from mice as compared with rats and humans. Our findings have implications for the use of mouse models to assess bone marrow toxicity for DNA-damaging agents and inhibitors of the DNA damage response. Finally, structural modeling of the PARP3-active site with different PARP inhibitors also highlights the potential to develop compounds with different PARP family member specificity profiles for optimal antitumor activity and tolerability. Cancer Res; 76(20); 6084-94. Ó2016 AACR.

Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas

“…Tumors from KB2P mouse donors were transplanted orthotopically into wild-type syngeneic mice, and when the tumor reached a volume >200 mm 3 , mice were treated with the PARPi AZD2461 for 28 consecutive days. Of note, PARPi AZD2461 is not a P-glycoprotein (Pgp) substrate, and therefore, acquired resistance to AZD2461 cannot be mediated by Pgp upregulation (Oplustil O’Connor et al, 2016). After an initial phase of response, the tumors eventually relapsed and were allowed to regrow to 100% volume, following which another treatment cycle was started.…”

Genetic Dissection of Cancer Development, Therapy Response, and Resistance in Mouse Models of Breast Cancer

“…2C,D). These events have also been known to mediate resistance in ovarian cancer patients (Swisher et al 2008;Patch et al 2015), showing the predictive potential of PDX models. The PDX models also revealed a novel resistance mechanism involving gene fusions that placed BRCA1 under transcriptional control of a heterologous promoter.…”

“…Although the clinical relevance of P-gp up-regulation as cause of drug resistance remains controversial (AmiriKordestani et al 2012), expression of MDR1, the human counterpart of Abcb1, was recently found to be inversely correlated to olaparib response in human ovarian cancer cells (Vaidyanathan et al 2016). Such increased expression may result from complex genomic rearrangements that fuse a distant promoter to the MDR1 gene and thereby bypass the MDR1 promoter methylation (Patch et al 2015). The case of P-gp shows that a thorough mechanistic understanding is instrumental to combat resistant tumors-for example, by coadministration of tariquidar or by switching treatment to chemotherapeutics that are poor substrates for P-gp (Jaspers et al 2013).…”

“…Alternatively, KB1P tumors were treated with the PARP inhibitor AZD2461, which is a poor substrate for P-gp (Oplustil O'Connor et al 2016). PARPi resistance developed in these models despite the exclusion of P-gp-related mechanisms.…”

PARP Inhibitors and DNA Repair: A Novel Beneficial Approach for Targeting Synthetic Lethal Tumor Cells

“…These include BMN 673 (Biomarin) (24), niraparib (25), rucaparib (26), veliparib (27), and AZD2461 (28). In addition, the efficacy of some PARP inhibitors has been identified in non-BRCA-mutation-linked cancers, including sporadic castration-resistant prostate cancer and non-smallcell lung cancer.…”