Abstract B27: CDK inhibition impairs homologous recombination and induces PARP inhibitor sensitivity via loss of c-myc expression in TNBC

Abstract

Abstract The c-myc oncogene is a “master regulator” amplified in several types of cancer including ovarian, breast, colorectal and pancreatic cancers. C-myc controls several cellular processes during tumor maintenance including the cell cycle, metabolism, and DNA damage repair while also playing an essential role in transforming normal cells during tumorigensis. C-myc amplification correlates with poor survival and a higher frequency of relapse in triple negative breast cancer (TNBC) patients. C-myc amplification promotes deregulation of the cell cycle, via transcriptional activation of G1-S-phase cell cycle and DNA replication genes. CDK inhibition has been shown to down regulate c-myc expression in cancer cells, in vitro. Therefore, we hypothesize that transient CDK inhibition downregulates c-myc expression and increases susceptibility to DNA damaging agents in TNBC cells. We observed the long-term response of several c-myc overexpressing TNBC cells to Dinaciclib, a potent CDK inhibitor (CDK 1, 2, 5, 9) in vitro. High Throughput Survival Assay (HTSA) analysis revealed that c-myc expressing TNBC cells have a potent response to CDK inhibition via Dinaciclib (IC50 10-20nM). Dinaciclib induces an S-phase arrest and downregulation of the c-myc/E2F1 pathway in both normal (MCF10A) and TNBC (MB231, SUM149, HCC1937) breast cancer cells. Loss of c-myc expression correlates with increased apoptosis in TNBC cells but not HMECs. C-myc downregulation also correlates with increased γH2AX DNA damage and downregulation of BRCA1 foci formation. The resultant impaired homologous recombination (HR) pathway in TNBC cells treated with Dinaciclib proposed an increased susceptibility to PARP inhibitor induced DNA damage. Combination Dinaciclib + PARP inhibition exhibited a Dinaciclib dose dependent synergistic growth inhibition of BRCA1 wild-type and mutant TNBC cells to PARP inhibitors. Dinaciclib also increased susceptibility of PARP inhibition in resistant BRCA1 mutant cell lines (HCC1937, SUM149). Dinaciclib + PARP Inhibitor combination therapy induced increased apoptosis, γH2AX DNA damage and decreased BRCA1, RAD51 foci formation. These results demonstrate that Dinaciclib + PARP inhibition induces growth arrest and induction of apoptosis in c-myc overexpressing cancer cells. C-myc is frequently amplified in TNBC tumors and may serve as a biomarker for CDK + PARP inhibitor combination therapy. Citation Format: Jason Patrick Carey, Khandan Keyomarsi. CDK inhibition impairs homologous recombination and induces PARP inhibitor sensitivity via loss of c-myc expression in TNBC. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B27.