Pharmacological mTOR targeting enhances the antineoplastic effects of selective PI3Kα inhibition in medulloblastoma

摘要: Despite recent advances in the treatment of medulloblastoma, patients high-risk categories still face very poor outcomes. Evidence indicates that a subpopulation cancer stem cells contributes to therapy resistance and tumour relapse these patients. To prevent relapse, development strategies tailored target subgroup specific signalling circuits medulloblastomas might be similarly important as targeting cell population. We have previously demonstrated potent antineoplastic effects for PI3Kα selective inhibitor alpelisib medulloblastoma. Here, we performed studies aimed enhance anti-medulloblastoma by simultaneous catalytic mTOR kinase. Pharmacological inhibition potently enhanced suppressive on proliferation, colony formation apoptosis additionally blocked sphere-forming ability medulloblastoma stem-like vitro. identified HH effector GLI1 dual SHH-type confirmed results HH-driven Ewing sarcoma cells. Importantly, pharmacologic greatly inhibitory growth vivo. In summary, findings highlight key role PI3K/mTOR regulation cancers suggest combined PI3Kα/mTOR may particularly interesting effective medulloblastomas.