ID #793 Combination of PRMT5 inhibitor and MEK inhibitor for targeting BRAF V600E mutation and MTAP loss in pediatric brain tumors
Shejuan An, Natalie Bizon, Alyssa Hohman, Mia Burton, Miriam BornhorstAbstract
Introduction
Approximately 70% of pediatric gliomas with a BRAFV600E mutation (BRAFV600E) has a co-occurring CDKN2A deletion, with a higher likelihood of tumor progression and decreased response to therapy. The MTAP gene is located adjacent to the CDKN2A gene and co-deletes with CDKN2A in more than 71% of these tumors. The loss of MTAP (MTAPdel) leads to the accumulation of MTA, which inhibits the activity of protein arginine methyltransferase 5 (PRMT5). This results in increased sensitivity to further PRMT5 inhibition, providing a new treatment target for patients with these genomic alterations.
Methods
To explore a new drug treatment combination for BRAFV600E/MTAPdel pediatric brain tumors, we analyzed the antitumor effects of PRMT5 inhibitors (PRMT5i) and MEK inhibitors (MEKi) on pediatric brain tumor cells with different genomic alterations in vitro.
Results
BRAFV600E/MTAPdel cells (BT40) are more sensitive to single drug treatment of MEKi and PRMT5i than BRAFwt/MTAPwt cells (7316-85A) (IC50 = 0.17 µM and >50 µM for MEKi, IC50 = 49.60 µM and >50 µM for PRMT5i, respectively). The combination treatment of MEKi (0.15 µM) with PRMT5i (50 µM) significantly inhibited cell viability at all time points (day 1, 2, 3, and 5) compared to single drug treatment in BT40 cells. Synergy analysis revealed that PRMT5i and MEKi have additive/synergistic effect on BT40 cells. We also tested BRAFV600E/MTAPwt cells (7316-870) and BRAFwt/MTAPdel cells (7316-7963 and 7316-8121), which had variable sensitivity to MEKi and PRMT5i treatment. Western blot showed inhibition of symmetric dimethylarginine mark (SDMA) and p-ERK expression following of PRMT5 and MEKi combination treatment.
Conclusion
The results suggested that combination of PRMT5i and MEKi might be a potential therapeutic strategy for the treatment of BRAFV600E/MTAPdel gliomas. Further in vivo confirmation studies are underway.