MTA协同型PRMT5抑制剂ABSK131与多种治疗药物联用在多种癌症模型中的协同抗肿瘤活性

Background: Homozygous deletion of MTAP occurs in ~10-15% of solid tumors and frequently coexists with major oncogenic drivers such as EGFR and KRAS , providing a strong rationale for combining their inhibitors with MTA-cooperative PRMT5 inhibitor. Moreover, low MTAP expression is linked to poorer survival in NSCLC treated with chemoimmunotherapy, underscoring the need for novel, effective therapeutic strategies in MTAP -deleted tumors. ABSK131, a highly potent and selective MTA-cooperative PRMT5 inhibitor discovered by Abbisko, is under clinical evaluation. Here, we investigated the potential of ABSK131 combined with multiple therapeutic agents to enhance antitumor efficacy across diverse cancer models preclinically. Methods: Synergistic activity of ABSK131 with various agents was evaluated using in vitro antiproliferative assays across various cancer cell lines, primarily from NSCLC and PDAC origins. Combination partners included chemotherapy agents and the inhibitors targeting KRAS, EGFR, MAT2A, etc. Synergy was quantified by combination index analysis. Prioritized combinations were further tested in xenograft models reflecting clinically relevant biomarker-defined contexts, including in combination with KRAS, EGFR inhibitors, and standard chemotherapy. Results: ABSK131 demonstrated strong in vitro synergy with multiple KRAS inhibitors in anti-proliferation assays. In KRAS -mutant and MTAP -deleted models, ABSK131 led to robust tumor growth inhibition when combined with KRAS G12C inhibitor AMG510 or KRAS G12D inhibitor ABSK141. In EGFR -mutant and MTAP -deleted NSCLC, ABSK131 combined with osimertinib produced enhanced anti-proliferative and in vivo antitumor efficacy. ABSK131 plus MAT2A inhibitor IDE397 induced consistent synergy across diverse cell types, indicating a broadly applicable mechanistic interaction. Additionally, synergy was observed with carboplatin in multiple NSCLC models in vitro and in vivo . Conclusion: ABSK131 synergizes with multiple therapeutic classes across MTAP -deleted models, providing compelling preclinical support for developing ABSK131-based combination strategies in genetically defined patient populations in clinic.