Abstract 3494: Characterizing the relationship between genotype and phenotype in DNA damage response-altered pancreatic cancer models

Abstract

Abstract Alterations in DNA damage response (DDR) proteins are prevalent across cancers and present unique opportunities for the therapeutic induction of synthetic lethality (i.e., two gene deficiencies in the same pathway synergize to kill tumor cells). In pancreatic adenocarcinoma, patients harboring alterations in DDR genes, such as in homology-directed repair (HDR), comprise the 10-20% of patients that may benefit from the recent FDA approval of Olaparib, a poly (ADP-ribose) polymerase inhibitor that disrupts non-homologous end joining (NHEJ). Despite being the best-in-class targeted therapy for DDR-altered pancreatic cancers, a subset of patients fails to respond to Olaparib and those that initially respond eventually go on to develop resistance. The mechanisms underlying resistance are poorly elucidated but suggest that some patients harboring DDR-altered tumors are HDR-proficient or revert to HDR-proficiency during therapy, bypassing the second gene deficiency requisite for synthetic lethal induction with targeted therapy (e.g., Olaparib). Utilizing patient-derived models of cancer, we are actively investigating DDR-altered, pancreatic tumor cell lines and exploring the relationship between DDR-alterations and HDR-deficiency with three goals: [1] To evaluate the prevalence of HDR-proficiency in BRCA-altered tumors, [2] to understand the extent to which patient-derived models of cancer are concordant and predictive of clinical outcomes, and [3] to identify novel therapeutic strategies for resistant patients. So far, we have observed HDR-proficiency by functional assays (e.g., RAD51 foci formation) in DDR-altered patient-derived cell lines that corresponds with poor response to Olaparib in vitro, and resistance to platinum therapy clinically. Whereas DDR-altered HDR-deficient lines had greater sensitivity to Olaparib and platinum therapy. These early data suggest that measures of HDR by functional assay may be more predictive of clinical therapeutic responses than the use of genetic signatures alone. Citation Format: James R. Carroll, Jason M. Link, Jonathan R. Brody. Characterizing the relationship between genotype and phenotype in DNA damage response-altered pancreatic cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3494.