Abstract A15: Downregulation of c-myc is synthetic lethal with PARP inhibitors in high MYC cancers independent of BRCA status

Abstract

Abstract PARP inhibitors represent a novel class of cancer therapeutics that exploit a synthetic lethal mechanism specific to cancer cells with a defect within the Homologous Recombination (HR) DNA repair pathway. Patients with a BRCA1/2 germ-line mutation have the highest response rate to PARP inhibitors. However, early clinical trial data has indicated that only ~30-40% BRCA mutant patients respond to PARP inhibitors. Coincidentally, the oncogene c-myc is the most frequently amplified gene in BRCA mutant tumors (~40-60%) which typically present as Triple Negative Breast Cancer (TNBC). The oncogene c-myc transcriptionally regulates several DNA repair genes, and correlates with poor survival among breast cancer patients. Therefore we hypothesized that dual combination therapy targeting c-myc and PARP is an effective therapeutic strategy in BRCA mutant tumors. C-myc siRNA induced increased sensitivity to PARP inhibitors in BRCA wild-type (MB231) & BRCA mutant (SUM149) TNBC cell lines and down regulated HR repair. Pan CDK inhibitor Dinaciclib demonstrated significant MYC inhibition across several TNBC cell lines. Additionally, Dinaciclib demonstrated synergistic growth inhibition in combination with PARP inhibitor Niraparib in both BRCA wild-type and mutant c-myc expressing TNBC cell lines. Combination therapy also leads to an increase in DNA damage (via γH2AX) with a decrease in HR repair (BRCA1/RAD51). TNBC cell line mouse xenografts demonstrated down regulation of c-myc and RAD51 in Dinaciclib + Niraparib treated tumors. Dual Dinaciclib + Niraparib therapy also induced synergistic growth inhibition in PARP inhibitor acquired resistant cell lines while demonstrating significant growth inhibition across a panel of c-myc overexpressing cancer cell lines (Ovarian, Prostate, Pancreatic, Colon & Lung). In conclusion, we demonstrated that dual CDK + PARP inhibition is synthetic lethal in both BRCA wild-type and mutant TNBC cell lines and is dependent upon down regulation of c-myc. This study supports c-myc as predictor of response to PARP inhibitor therapy and may also serve as a biomarker of response to Dinaciclib + PARPi therapy in high MYC expressing tumors. Citation Format: Jason PW Carey, Smruthi Vjayaraghavan, Kelly Hunt, Khandan Keyomarsi. Downregulation of c-myc is synthetic lethal with PARP inhibitors in high MYC cancers independent of BRCA status [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A15.