Abstract 2052: TRIP13 amplification confers PARP inhibitor resistance and polymerase theta inhibitor sensitivity

Abstract

Abstract Genome integrity is critical for cellular survival and is maintained by DNA repair pathways collectively known as the DNA damage response (DDR). Double-stranded breaks (DSBs) are the most deleterious form of DNA damage and can be repaired through homologous recombination (HR), non-homologous end-joining (NHEJ), and microhomology-mediated end-joining (MMEJ). The first step in both HR and MMEJ is resection of the DNA DSB termini to create single-stranded DNA 3' overhangs. In contrast, the 53BP1-Shieldin complex limits DNA end-resection and promotes NHEJ. Defects in HR repair can be present in cancer cells secondary to germline or somatic mutations in BRCA1, BRCA2, or other genes in the HR pathway, and such defects confer sensitivity to inhibitors of poly (ADP-ribose) polymerase (PARP). Resistance to PARP inhibitors can occur if there is loss of the 53BP1-Shieldin complex or amplification of TRIP13, a negative regulator of the 53BP1-Shieldin complex (Clairmont, et al. NCB 22:87, 2020). Here, we show that cells with TRIP13 amplification have increased DNA end-resection and increased expression of polymerase theta (POLQ), the critical enzyme for MMEJ. The resulting increase in POLQ activity limits DNA end-resection and increases MMEJ-mediated DSB repair. In these cells, inhibition of POLQ by a POLQ inhibitor, novobiocin (Zhou, et al. bioRxiv, 2020), resulted in excessive DNA end-resection, replication stress, activation of the ataxia-telangiectasia and Rad3 related (ATR) DNA damage response, and ultimately cell death. Conversely, knockdown of TRIP13 promotes PARP inhibitor sensitivity and POLQ inhibitor resistance. Thus, TRIP13 amplification may function as a biomarker for resistance to PARP inhibitors and sensitivity to a POLQ inhibitor. In summary, these results reveal a mechanism of PARP inhibitor resistance and POLQ inhibitor sensitivity in HR-deficient cells, provide a rationale for using TRIP13 as a biomarker for PARP inhibitor or POLQ inhibitor sensitivity, and may offer novel therapeutic strategies for PARP inhibitor resistant cancers. Citation Format: Jeffrey Patterson-Fortin, Jia Zhou, Alan D'Andrea. TRIP13 amplification confers PARP inhibitor resistance and polymerase theta inhibitor sensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2052.