Abstract 1422: Enhancing the therapeutic effects of PARP inhibitors in combination DNA methyl transferase inhibitors, using low doses of ionizing radiation in non small cell lung cancers

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths in the US. Treatment most commonly relies on ionizing radiation (IR) and platinum-based DNA damaging agents, but long-term survival is poor and patients tend to suffer chronic side-effects due to the high radiation dose to the surrounding normal tissues. Therefore, new treatments are needed that can be used in combination lower radiation doses. We have recently reported that low, non-cytotoxic doses Poly ADP ribose polymerase inhibitors (PARPi) Talazoparib in combination with DNA methyltransferase inhibitors (DNMTi) Decitabine (DAC) or azacytidine (AZA) significantly increase cytotoxicity in acute myeloid leukemia and breast cancer models in vitro and anti-tumor effects in vivo. Simultaneous administration of both inhibitors result in increased PARP binding in DNA, leading to higher levels of DNA double strand breaks (DSBs), yielding increased cytotoxicity, compared with each agent treatment alone. We first studied the efficacy of Talazoparib and AZA combination therapy in multiple NSCLC cell lines (A549, H358 and H838) in vitro through colony forming assays. Results showed, compared to single agent treatments, combination drug treatment significantly decreased colony formation. Cell viability was also significantly decreased with the drug combination in MTS assays (P Citation Format: Christopher Biondi, Daniel Fontaine, Lora Stojanovic, Pratik Nagaria, Rena Lapidus, Eun Yong Choi, Javed Mahmood, Stephen Baylin, Feyruz V. Rassool. Enhancing the therapeutic effects of PARP inhibitors in combination DNA methyl transferase inhibitors, using low doses of ionizing radiation in non small cell lung cancers [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 1422. doi:10.1158/1538-7445.AM2017-1422