Abstract B132: MAT2A inhibition enhances the anti-tumor efficacy of combined pan-RAS(ON) and PRMT5 inhibition in MTAP-deficient pancreatic tumors
Bin Liu, Lu Li, Yulai Zhang, Changhong Jia, Shuang Wang, Lu Chang, Yulun Wu, Zhizhong Li, Amy Guan, Yongqi GuoAbstract
Background:
The prevalence of both MTAP deletion and RAS mutations in pancreatic cancer is approximately 30∼40%. Dual inhibition of both pathways represents a promising therapeutic strategy. Preclinical and early clinical evidence supports the application of combined MTA-cooperative PRMT5 inhibitor and pan-RAS(ON) inhibitor in PDAC. However, it remains unclear whether incorporating MAT2A inhibition—as a mechanistically rational backbone therapy for MTAP-del tumors—could further enhance anti-tumor efficacy. MAT2A inhibition reduces SAM levels, which could enhance the sensitivity to PRMT5MTA inhibitors in MTAP-del tumors. Here we present the discovery of a highly brain-penetrant and potent MAT2A inhibitor, PH050, and report that its combination with PH033, a molecular glue pan-RAS(ON) inhibitor with tumor-enriched distribution properties, enhanced the anti-tumor activity.
Objective&Method:
Comprehensive in vitro and in vivo PD studies have been conducted to demonstrate the potency of PH050, and combination effect of PH050 with PH033, with or without PRMT5MTA inhibitor (MRTX1719). Potency and selectivity was accessed in a panel of MTAP-deltumor cells and in isogenic cell pairs, respectively. The synergistic effects of the two-agent (PH050+PH033) or three-agent (PH050+PH033+MRTX1719) combination were evaluated in several pancreatic cancer xenograft models.
Results:
Single-agent activity: Biochemically, nanomolar concentrations of PH050 effectively inhibited MAT2A enzyme and reduced intracellular SAM level in MTAP-del tumor cells. It suppressed cell proliferation in more than 10 MTAP-del tumor cell lines with IC50 values ranging from 40 to 654 nM. The IC50 ratio in MTAP-WT and MTAP-del isogenic cells was ∼1500-fold. After a single dose, a >90% and >70% decrease in SAM levels in tumors and in the brain was observed, respectively. PH050 demonstrated anti-tumor efficacy in pancreatic xenograft models with MTAP-del and RAS mutations. Combination Efficacy: MAT2A inhibitor PH050 when combined with pan-RAS(ON)i, produced enhanced tumor suppression than either monotherapy in MTAP-del pancreatic tumor models at well-tolerated doses. Notably, compared with MAT2Ai+pan-RAS(ON)i or PRMT5i+pan-RAS(ON)i, the triple combination (MAT2Ai+pan-RAS(ON)i+PRMT5i) elicited best tumor growth suppression and prolonged response without causing significant body weight loss.
Conclusions:
PH050 is a potent, selective and brain penetrant MAT2A inhibitor. The preclinical studies indicate that the combination of PH050 and pan-RAS(ON) inhibitor (with or without PRMT5MTA inhibitor) has the potential to exert profound and durable therapeutic benefit in patients with MTAP-deleted pancreatic cancer.
Citation Format:
Bin Liu, Lu Li, Yulai Zhang, Changhong Jia, Shuang Wang, Lu Chang, Yulun Wu, Zhizhong Li, Amy Guan, Yongqi Guo. MAT2A inhibition enhances the anti-tumor efficacy of combined pan-RAS(ON) and PRMT5 inhibition in MTAP-deficient pancreatic tumors [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr B132.