Abstract 6488: Dual targeting of PARP and RAS enhances antitumor activity in pancreatic cancer

Abstract KRAS is the most frequent oncogenic mutation in PDAC. KRAS drives tumorigenesis and enhances mechanisms of DNA-damage repair (DDR). Specifically, KRAS upregulates HR and non-homologous end joining (NHEJ), which are critical pathways for DNA repair. Dual inhibition of these two driver pathways in BRCAmut PDAC, the MAPK/KRAS and the DDR, may have a promising therapeutic effect. However, this effect may be also exploited in the general PDAC population. PARP and RAS combined inhibition may extend and deepen therapeutic effect and delay emergence of therapeutic resistance.Our main goal was to examine the therapeutic effect of PARP and RAS(ON) combined inhibition on tumor growth in BRCAmut and BRCA-WT preclinical models. We established pre-clinical patient derived xenografts (PDX) models (n=160), PDX derived cells (n=37) and 3D organoids (n=11). Models were analyzed by WGS and RNAseq. We tested the effect of PARPi (olaparib) in combination with two RAS inhibitors: A tool RAS(ON) -multi-selective inhibitor RMC-7977 and a tool RAS(ON) G12D-selective inhibitor RMC-9945 (RM-044) in-vitro and in-vivo, utilizing specific models’ systems based on BRCA and KRAS status (n=12).In vitro, PDCs were treated with olaparib, RMC-7977, RMC-9945 and combinations for 5 days. A dose response curve was observed for each cell line, with a variability of response between cell lines. Combination of RAS(ON)i and olaparib exhibited significant additive effect. In 3D organoids, combinational treatment of olaparib and RMC-7977 demonstrated a profound effect on viability. This effect was noted on BRCAmut and BRCA-WT cell lines. In-vivo experiment in a platinum sensitive BRCA2 mutated PDX model both RMC-7977 and RMC-9945 significantly attenuated tumor growth rate compared to control (p0.05). The combination demonstrated a comparable effect to PARPi monotherapy. Yet, a tendency towards an enhanced response was observed by ex-vivo tumor volume and tumor weight. We hypothesize that a longer duration of experiment (currently being performed) will enhance response and delay the emergence of therapeutic resistance. In parallel mechanistic functional assays are being performed. Overall, we demonstrate a superior effect of the combination of PARPi and RAS(ON)i on PDAC using patient-derived models in-vitro (BRCAmut and BRCA WT) and in-vivo (BRCAmut). Notably, most models were generated from tumors obtained from patients at clinical resistance to standard of care treatment reflecting models with aggressive biology. Thus, these findings support further evaluation of combinational treatment of both RAS(ON) and PARP inhibition in this population. Citation Format: Chani Stossel, Gali Altman, Dikla Atias, Yulia Glick Gorman, Hanita Ovadia, Liora Chouchan, Elina Haimov-Talmoud, Maria Raitses-Gurevich, Tamar Beller, Talia Golan. Dual targeting of PARP and RAS enhances antitumor activity in pancreatic cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6488.