Abstract A048: PRC2 inhibition enhances KRAS inhibitor response to delay treatment relapse in KRAS-mutant preclinical lung and colorectal cancer models

Abstract Background: Polycomb repressive complex 2 (PRC2) silences transcription by tri-methylating histone H3 at lysine 27, to regulate cell growth and differentiation. We demonstrated that PRC2 and androgen receptor (AR) inhibitors promote durable antitumor activity in prostate cancer models by suppressing the evolution of lineage escape pathways, driving cell differentiation, leading to reprogrammed cells that depend on oncogenic AR signaling. Recent work has further implicated PRC2 in enabling cell plasticity in other cancers. For example, in triple-negative breast cancer, combining EZH2 with AKT inhibitors induced differentiation, triggering cell death through mechanisms akin to mammary gland involution. Similarly, in KRAS-mutant colorectal cancer (CRC) models, concurrent PRC2 and MAPK pathway inhibition induced cell differentiation and impaired tumor growth. KRAS inhibitor resistance can arise by non-genetic reprogramming and transcriptional plasticity. Given that PRC2 inhibition, as shown with ORIC-944 in prostate cancer models, may overcome treatment resistance by restricting access to plasticity program genes, we investigated the impact of combined KRAS and PRC2 inhibition in KRAS-mutant CRC and non-small cell lung cancer (NSCLC). Methods: ORIC-944 is a next-generation, potent, highly selective, orally bioavailable small molecule inhibitor of PRC2 that allosterically targets the EED subunit, with potential best-in-class drug properties including superior half-life and reduced drug-drug interaction liabilities. In vitro and in vivo studies across KRAS-mutant NSCLC and CRC models were used to evaluate ORIC-944 and KRAS inhibition. The mechanism of PRC2 inhibition was profiled using RNA- and ATAC-sequencing. Results: Evaluation of combined KRAS inhibition and PRC2 inhibition with ORIC-944 was performed in KRAS-mutant cell line xenograft models in vivo. The combination of adagrasib, a KRAS G12C inhibitor, and ORIC-944 resulted in greater antitumor efficacy, more tumor regressions, and significantly smaller tumors, in both CRC and NSCLC models. Moreover, combining ORIC-944 with KRAS inhibition delayed KRAS inhibitor relapse and prolonged progression-free survival (PFS) in both models. In vivo NSCLC findings confirmed in vitro, where ORIC-944 combined with KRAS inhibition further reduced proliferation and viability effects vs. single agent KRAS inhibition. Gene expression analysis confirmed strong PRC2 inhibition with ORIC-944 across xenograft studies and reduced cell cycle and G2M signatures were the most prominent common feature of the combination. In the CRC model, ORIC-944 induced enrichment of secretory lineage conversion, which was sustained with combination treatment. Conclusions: Combining ORIC-944 with KRAS inhibition significantly improved efficacy and PFS in NSCLC and CRC models, demonstrating that PRC2 inhibition can deepen and extend KRAS inhibitor responses to prevent or delay resistance to KRAS inhibition. ORIC-944 is under clinical evaluation in a global Phase 1b study (NCT05413421). Citation Format: Stephanie W. Ni, Natalie Yuen, Livia Ulicna, Denise F. Reyes, Michal Pawlak, Frank L. Duong, Jason E. Long, Aleksandr Pankov, Lori S. Friedman, Anneleen Daemen, Melissa R. Junttila. PRC2 inhibition enhances KRAS inhibitor response to delay treatment relapse in KRAS-mutant preclinical lung and colorectal cancer models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A048.