Inactivation of PRMT5 by PARP Inhibitors Confers High Susceptibility in MTAP-Deficient Cancers

Background: Methylthioadenosine phosphorylase (MTAP) deficiency caused by homozygous deletion is prevalent in solid tumors and contributes to malignant progression, thereby rendering cancer cells vulnerable to dysfunction of protein arginine methyltransferase 5 (PRMT5). This study aimed to investigate whether Poly (ADP-ribose) polymerase (PARP) inhibitors could exploit this vulnerability through PRMT5 inactivation in MTAP-deficient tumors. Methods: PRMT5 activity was assessed in vitro and in vivo following PARP inhibitor treatment. The antitumor effects of PARP inhibitors alone or in combination with either the MTAP inhibitor MTDIA or the PRMT5 inhibitor EPZ015666 were evaluated in solid tumor models, including MTAP-deficient tumor models in vivo. Results: PARP inhibitors effectively inactivated PRMT5 in vitro and in vivo and exacerbated DNA double-strand breaks induced by PARP inhibition. Moreover, PARP inhibitors showed significant synergistic effects when combined with either MTDIA or EPZ015666 in solid tumor models. MTAP-deficient tumors exhibited increased vulnerability to olaparib in vivo, and combined treatment with olaparib plus MTDIA or EPZ015666 produced improved therapeutic outcomes compared with olaparib alone. Conclusions: These findings identify PARP inhibitors as a potential therapeutic strategy for MTAP-deficient tumors through targeted inactivation of PRMT5 and support further evaluation of PARP inhibitor-based combination therapies in this molecular context.