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. Combining MAPKi with X-ray therapy (XRT) has the potential to improve the cure rate, but development of therapeutic resistance poses a major challenge. Methods XRT resistance was induced by admnistration of multiple cycles of radiation in vivo in pediatric BRAFV600E glioma patient-derived xenograft (PDX) models. RNA sequencing was performed to identify differentially expressed genes and pathways that potentially contribute 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 rapidly following multiple cycles of XRT. MEK inhibition Combining XRT significantly increased the tumor control, compared to XRT alone, but resistance to combined therapy developed rapidly. RNA-sequencing analysis revealed upregulation of MAPK and PI3K-mTOR signaling pathways in the radiation resistant tumors. Cells isolated from radiation resistant tumor tissue showed resistance to XRT in vitro, and resistance was partially reversed by inhibiting PI3K/mTOR signaling. Upregulation of TORC1 signaling in parental XRT-naïve tumor cells, by expressing constitutively active AKT, or by deleting the negative regulator TSC2, conferred resistance to XRT in vitro. 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 brain tumor PDX models, and, more importantly, prevented or delayed the development of radiation resistance. Conclusion PI3K/mTOR activation promotes the development of radiation resistance in pediatric BRAFV600E gliomas. Dual targeting of MAPK and TORC1 signaling significantly enhances the therapeutic efficacy of XRT, and can potentially prevent the development of radiation resistance.
Li et al. (Fri,) studied this question.