Abstract PL03-01: Targeting DNA Repair and Defective DNA repair

Abstract

Abstract Genomic instability and defective DNA repair (DDR) are key hallmarks of many currently incurable malignancies, with these often associating with poorer outcomes and more aggressive disease. DDR supports tumor evolution but can generate genomic alterations leading to neoantigen generation from single nucleotide alterations and genomic rearrangements/fusions, which may lead to tumor sculpting by immune responses and tumor cell adaptations to abrogate anticancer immune responses through not only immune checkpoint expression but also the secretion of cytokines and chemokines that impact immune cell migration and function. Multiple studies have now shown that DDR can be a vulnerability, both through synthetic lethal strategies with drugs like PARP and ATR inhibition and DNA damaging agents, as well as through strategies targeting the immune response as best exemplified by mismatch repair defects and PD-1 targeting and more recently emerging evidence on CDK12 alterations. This presentation will focus on the therapeutic targeting of tumors with DNA repair defects, synthetic lethal strategies, and the challenges of developing anticancer drugs targeting DNA repair. Citation Format: Johann de Bono. Targeting DNA Repair and Defective DNA repair [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr PL03-01. doi:10.1158/1535-7163.TARG-19-PL03-01