Abstract 6226: Therapeutic vulnerability of MTAP-deleted nasopharyngeal carcinoma by MAT2A inhibitors

Abstract Introduction: EBV-associated nasopharyngeal carcinoma (NPC) is a distinct type of head and neck cancer that is prevalence in southern China and Southeast Asia. While radiotherapy or concurrent chemo-radiotherapy are efficient for the patients with early disease, more than 60% of NPC patients are diagnosed at an advanced stage and frequently develop local failure and distant metastases. The lack of druggable targets is a challenge for controlling this common cancer. By whole-genome sequencing and FISH analysis, we have defined the frequent homozygous deletion of 9p21.3 in NPC. The loss of MTAP that encodes methylthioadenosine phosphorylase on this region was found in 32% and 34% of primary and recurrent NPC respectively, indicating vulnerability to targeted-therapies for MAT2A/PRMT5 axis. Methods: The preclinical efficacy of MAT2A inhibitors, FIDAS-5 and BT115386 was elucidated in a panel of MTAP-deleted EBV-positive NPC cell lines and patient-derived xenografts. In vitro and in vivo growth inhibition of NPC cells by these compounds were determined. In addition to the suppression of PRMT5 activity, the effects of MAT2A inhibitor treatment on activating p53 pathway, inducing EBV lytic genes and modulating expression of proteins involved in cellular differentiation, apoptosis and lipogenesis in NPC were accessed. Results: In vitro study has revealed that treatment of the MAT2A inhibitors markedly reduced PRMT5 activity and cell growth in all MTAP-deleted NPCs. Compared to the MTAP-wild type NPC cells, the MTAP-deleted cells, either with wild type or mutated TP53, showed heightened sensitivity (>9 fold more sensitive) to the MAT2A inhibition by FIDAS-5 and BT115386. The potent in vivo growth inhibitory effect of BT115386 were observed in the MTAP-deleted xenografts, but not in that with wild type MTAP. In the MTAP-deleted NPC treated with MAT2A inhibitors, activation of p53 pathway and induction of BAX apoptotic protein were consistently found. The treatment also promoted differentiation, suppressed stemness transcription factors and inhibited lipogenesis. Notably, the MAT2A inhibitors also disrupted EBV latency in the MTAP-deleted NPC, induction of multiple EBV lytic genes including BZLF1 and BMRF1 were demonstrated. Conclusion: Selective sensitivity of MTAP-deleted NPC to the treatment of MAT2A inhibitors including FIDAS-5 and BT115386 was demonstrated. To facility its growth inhibitory effects, the compounds targeted PRMT5 activity, subsequently modulated multiple cellular mechanisms and induced EBV lytic reactivation. The potent antitumor effect of BT115386 was demonstrated in the in vivo MTAP-deleted NPC mouse models. The findings warrant future assessments of MAT2A inhibitors in clinical studies for NPC, which might well impact a large subset of patients. Acknowledgment: Acknowledgment: The work was supported by Hong Kong RGC funding (GRF:14101721 and AoE/M-401/20) and HMRF grant (#09203176) Citation Format: YUK-Yu Chan, Chi-Man Tsang, Grace T.Y. Chung, Ka-Fai To, Yi Zhang, Xiaodong Zhang, Jun Tang, Kwok Wai Lo. Therapeutic vulnerability of MTAP-deleted nasopharyngeal carcinoma by MAT2A inhibitors [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 6226.