Abstract LB098: Vulnerability of MTAP-deleted nasopharyngeal carcinoma to MAT2A inhibition

Nasopharyngeal carcinoma (NPC) is an EBV-associated cancer prevalent in Southern China and Southeast Asia. We have generated a comprehensive genomic profile of NPC using whole-genome sequencing (WGS) and established a catalogue of somatic alterations of this EBV-associated cancer. In addition to the significantly mutated genes reported in previous WES studies, our WGS study revealed recurrent structural variants (SVs) and copy number variants (CNVs) driving key oncogenic pathways, including cell cycle, NF-kappaB and TGF-beta signaling. While immediately druggable gene aberrations (e.g. PIK3CA mutations and FGFR3-TACC3 fusions) are found in only ~3-5% of NPC, a synthetic lethality-based target, homozygous deletion of MTAP defined by fine-mapping of CDKN2A/CDKN2B deletion breakpoints at chromosome 9p21.3 was frequently detected (34%). Notably, the study has also revealed mutual exclusivity among tumors with MTAP deletion and TP53 alterations (p=0.022). Loss of MTAP has further been validated in a cohort of advanced and recurrent tumors (16/50, 32%) by FISH analysis and immunohistochemistry staining. The high prevalence and clonal nature of MTAP deletion in NPC implicate synthetic lethal targeting of MTAP-deleted tumors as a potential precision treatment for NPC patients. Using a CRISPR-based MTAP-knockout cell line and MTAP-deleted patient derived xenograft (PDX), we revealed that MAT2A and PRMT5 inhibition selectively suppressed growth of MTAP-deleted NPC. Treatment with MAT2A inhibitor, FIADS-5, led to depleted PRMT5 activity and reduced symmetric arginine methylation (SAMe) in these in vitro and in vivo NPC models. In addition to selective growth inhibition, MAT2A inhibition also targeted various unique oncogenic properties in NPC. The FIADS-5 treatment was shown to induce TP53 and BAX expression, cellular differentiation and keratinization in these MTAP-deleted NPC. Our findings demonstrated the translational potential of targeting MTAP-deletion in this EBV-associated epithelial cancer. Citation Format: Yuk Yu Chan, Jeff P. Bruce, Vivian W.Y. Lui, Grace T. Y. Chung, Sai-Wah Tsao, Ka-Fai To, Trevor J. Pugh, Kwok-Wai Lo. Vulnerability of MTAP-deleted nasopharyngeal carcinoma to MAT2A inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB098.