Abstract 6278: Combination therapeutic strategy with type I PRMT inhibition in cancer treatment

Abstract

Abstract Type I protein arginine methyltransferases (PRMTs) are highly expressed and associated in various tumors. Targeting PRMTs as an epigenetic modulation could be valuable for treating cancer when combined with other therapies. We identified a series of orally bioavailable small molecule type I PRMT inhibitors with demonstrated single and combination anti-tumor efficacy in a variety of scenarios or models. Firstly, mutations of RNA splicing factors (SFs) commonly occur in hematologic malignancies and a variety of solid tumors, resulting in vulnerability to further disruption of the spliceosome. Inhibiting symmetric or asymmetric dimethylation of arginine could alter the RNA-binding specificity of the SFs and lead to the preferential killing of SF-mutant leukemias over wild-type counterparts (Fong et al., 2019). Therefore, targeting type I protein arginine methyltransferases (PRMTs) and PRMT5 concomitantly could minimize the compensatory effects and synergistically enhance antitumor activity. We validated the synergistic effects and mechanisms of combined treatment with a type I PRMT inhibitor and a PRMT5 inhibitor (JNJ-64619178, GSK3326595/EPZ015938 or an in-house PRMT5i) using cell-based assays and in vivo studies. Secondly, Methionine Adenosyltransferase 2A (MAT2A) inhibition decreases formation of S-adenosylmethionine (SAM), the cofactor of PRMTs, could in turn sensitize cancer cells to type I PRMT inhibition. In vitro and in vivo studies revealed that inhibitors of type I PRMT and MAT2A (AG-270) dosing combination indeed exhibited stronger anti-cancer activity than mono-treatment. Thirdly, the arginine methylation of receptor tyrosine kinases (RTKs) mediated by type I PRMT could increase the therapeutic sensitivity to RTK inhibitors like FLT3i. PRMT1 overexpression may contribute to AML stem/progenitor cells survival possibly through FLT3-ITD methylation, which may lead to enhanced activation of downstream signaling for cell survival and impact the regulation of self-renewal genes in leukemic initiating cells (LIC) (He et al, 2018). Hence, the combination treatment of FLT3 and type I PRMT inhibitors may provide a broader therapeutic benefit on FLT3 mutated and/or overexpressed Acute Myeloid Leukemia (AML). In vitro, strong combination synergy was observed with a remarkable induction of cell death. In vivo, the combination of type I PRMT inhibitor with different FLT3 inhibitors (Gilteritinib, Midostaurin, or CTS2016) led to deeper antitumor responses in a variety of FLT3-ITD AML models. Taken together, these findings support the co-administration of type I PRMT inhibitor with various therapies including epigenetic reprogramming, cancer metabolism modulation, or targeted therapies for receptor tyrosine kinases, which could benefit cancer patients as a promising therapeutic strategy. Citation Format: Hui Shi, Xingnian Fu, Yilin Liu, Qiugeng Ouyang, Meng Wang, Jiaxin Huang, Long Wang, Youzhen Wang, Yuan Mi, Haiping Wu. Combination therapeutic strategy with type I PRMT inhibition in cancer treatment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6278.