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Activation of the RAS-MAPK signaling cascade is common in pediatric gliomas. Based on the role of SHP2 in RAS pathway signaling, we hypothesized that NF1-deficient pediatric glioma models would respond to SHP2 inhibitor monotherapy whereas BRAF-V600E gliomas would not. However, we postulated that the latter would exhibit increased sensitivity to a BRAF inhibitor (BRAFi) in combination with SHP2i. Here we demonstrate that the SHP2 inhibitors SHP099 and RMC-4550 (SHP2i) show significant single-agent activity in vitro against NF1-deficient glioma cells and that the combination of RMC-4550 with BRAFi shows increased activity in BRAF-V600E glioma cells relative to the single-agents. METHODS Using a panel of NF1 mutant/deficient and BRAF-V600E mutant glioma cell lines we examined effects on cell viability and protein expression levels of total and phosphorylated MEK, ERK, and AKT. RESULTS LN229 and U87 NF1-deficient glioma cells are sensitive to SHP2i alone but not A375 cells (melanoma, BRAF-V600E). Additionally, we show that in multiple BRAF-V600E glioma cell lines BRAFi sensitivity increases when combined with a SHP2i. Immunoblots show decreased expression of pERK and pMEK in LN229 cells following SHP2i exposure, while A375 cells maintain MAPK pathway signaling. A sustained decrease in the expression of pERK after 24 hours was observed in BRAF-V600E glioma cells with BRAFi in combination with SHP2i, consistent with relief of feedback inhibition. In vivo studies using orthotopic xenograft models are underway. CONCLUSION SHP2i shows preclinical activity in vitro against NF1-deficient pediatric glioma cell lines as a single-agent and against BRAF-V600E gliomas in combination with BRAFi.

MODL-17. SHP2 INHIBITORS SHOW ACTIVITY AGAINST NF1-DEFICIENT GLIOMAS AND ENHANCE MAPK PATHWAY INHIBITION IN BRAF-V600E MUTANT GLIOMAS