Abstract
BACKGROUND: MAPK pathway inhibitors (MAPKi) have shown significant efficacy in treating childhood BRAF-activated brain tumors. For tumors harboring BRAFV600E mutations, the drugs are rarely curative, and patients can become refractory to treatment. MAPKi combining X-radiation therapy (XRT) may improve cure rate, but the development of XRT resistance is a challenge. METHODS: XRT resistance was induced by multiple XRT cycles in pediatric BRAFV600E glioma patient-derived xenograft (PDX) models. RNA sequencing was performed to identify differentially expressed genes and pathways potentially contributing to XRT resistance. Cells isolated from PDXs were used to test the contribution of specific genes and pathways to XRT resistance. PDX models were used to evaluate the efficacy of targeted treatments combined with XRT. RESULTS: Tumors developed resistance after multiple cycles of XRT. MEK inhibition combining XRT significantly improved tumor control compared to XRT alone, but resistance to combined therapy developed rapidly. RNA sequencing analysis revealed up-regulation of MAPK and PI3K-mTOR signaling in the XRT-resistant tumors. Isolated cells showed in vitro resistance to XRT, which was partially reversed by inhibiting PI3K-mTOR. Up-regulation of TORC1 signaling in XRT naïve tumor cells, via constitutively active Akt or TSC2 deletion, conferred in vitro XRT resistance. The pro-survival gene BIRC5 (Survivin), a target of TORC1 signaling, contributed to XRT resistance. Combining trametinib-rapamycin with XRT significantly enhanced therapeutic efficacy in PDX models and prevented or delayed resistance development. CONCLUSION: PI3K-mTOR activation promotes the development of XRT resistance in pediatric BRAFV600E glioma. Dual targeting of MAPK and TORC1 signaling significantly enhances the therapeutic efficacy of XRT and can potentially prevent the development of XRT resistance.