Abstract 2744: Synthetic lethal killing of RAD54B-deficient cancer cells by PARP1 silencing and inhibition

Abstract Colorectal Cancer (CRC) is the second leading cause of cancer-related deaths in North America. Currently, many chemotherapeutics are non-specific and preferentially kill cancer cells based on their high proliferation rate. However, due to the lack of tumor specificity, many treatments have unwanted side effects. Accordingly, identifying novel therapeutic strategies and drug targets that better target and combat cancer are needed. To address this need, synthetic lethal (SL) approaches are now being explored in many cancer contexts. Synthetic lethality refers to the lethal combination of two independently viable mutations and functions by exploiting the aberrant genetics contained within cancer cells. RAD54B is an excellent candidate to exploit using a SL paradigm as it normally functions in homologous recombination repair (HRR) and hypomorphic expression and/or function are implicated in tumorigenesis in a wide array of cancers. We predict that RAD54B and PARP1 are SL, as BRCA1 and BRCA2, which also encode functions within HRR, are SL with PARP1. To identify PARP1 as a novel SL interactor of RAD54B, we employed an established RNAi-based screening approach along with a RAD54B isogenic CRC model. Conceptually, following PARP1 silencing, a SL interaction will result in fewer cells within the RAD54B-deficient cells relative to RAD54B-proficient controls. Accordingly, we sought to determine whether PARP1 silencing or inhibition (Olaparib or BMN673) would induce selective killing within RAD54B-deficient HCT116 cells relative to controls. As predicted, PARP1 silencing with either individual or pooled siRNA duplexes and inhibition with both Olaparib and BMN673 was associated with statistically significant decreases in the number of RAD54B-deficient cells relative to controls. To confirm the SL interaction did not occur due to de novo mutations within the RAD54B-deficient cells, dual silencing of RAD54B and PARP1 was performed within the parental line and confirmed the above findings. Finally, real-time cellular analyses were conducted and revealed the decrease in cell numbers was due to cellular cytotoxicity rather than cell cycle arrest. Collectively, these data show that RAD54B and PARP1 are SL, and identify PARP1 is a candidate lead target in CRCs harboring RAD54B defects. Citation Format: Erin N. McAndrew, Chloe C. Lepage, Kirk J. McManus. Synthetic lethal killing of RAD54B-deficient cancer cells by PARP1 silencing and inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2744.