Molecular rationale for the use of PI3K/AKT/mTOR pathway inhibitors in combination with crizotinib in ALK-mutated neuroblastoma
Copyright policy )Molecular rationale for the use of PI3K/AKT/mTOR pathway inhibitors in combination with crizotinib in ALK-mutated neuroblastoma
Mutations in the ALK tyrosine kinase receptor gene represent important therapeutic targets in neuroblastoma, yet their clinical translation has been challenging. The ALK(F1174L) mutation is sensitive to the ALK inhibitor crizotinib only at high doses and mediates acquired resistance to crizotinib in ALK-translocated cancers. We have shown that the combination of crizotinib and an inhibitor of downstream signaling induces a favorable response in transgenic mice bearing ALK(F1174L)/MYCN-positive neuroblastoma. Here, we investigated the molecular basis of this effect and assessed whether a similar strategy would be effective in ALK-mutated tumors lacking MYCN overexpression. We show that in ALK-mutated, MYCN-amplified neuroblastoma cells, crizotinib alone does not affect mTORC1 activity as indicated by persistent RPS6 phosphorylation. Combined treatment with crizotinib and an ATP-competitive mTOR inhibitor abrogated RPS6 phosphorylation, leading to reduced tumor growth and prolonged survival in ALK(F1174L)/MYCN-positive models compared to single agent treatment. By contrast, this combination, while inducing mTORC1 downregulation, caused reciprocal upregulation of PI3K activity in ALK-mutated cells expressing wild-type MYCN. Here, an inhibitor with potency against both mTOR and PI3K was more effective in promoting cytotoxicity when combined with crizotinib. Our findings should enable a more precise selection of molecularly targeted agents for patients with ALK-mutated tumors.
- National University of Singapore Singapore
- Harvard University United States
- Harvard Medical School United States
- National University of Singapore Libraries Singapore
- Rowland Institute at Harvard United States
drug megadose, mTOR inhibitor, Mice, SCID, 2 morpholino 8 phenylchromone, gedatolisib, Neuroblastoma, nuclear protein, Mice, Inbred NOD, MYCN, Antineoplastic Combined Chemotherapy Protocols, multiprotein complex, Anaplastic Lymphoma Kinase, phosphatidylinositol 3 kinase, gene mutation, Molecular Targeted Therapy, pyrazole derivative, antineoplastic agent, Oncogene Proteins, N-Myc Proto-Oncogene Protein, protein kinase inhibitor, drug cytotoxicity, target of rapamycin kinase, Nuclear Proteins, anaplastic lymphoma kinase, MTOR protein, unclassified drug, mechanistic target of rapamycin complex 1, enzyme activity, oncoprotein, MYCN gene, molecularly targeted therapy, down regulation, drug potency, pictilisib, 570, animal experiment, 610, pyridine derivative, antineoplastic activity, Mechanistic Target of Rapamycin Complex 1, Article, multiple cycle treatment, neuroblastoma, MYCN protein, Crizotinib, Cell Line, Tumor, protein S6, gene expression profiling, Animals, Humans, dactolisib, controlled study, human, ALK gene, mouse, crizotinib, mammalian target of rapamycin inhibitor, nonhuman, torin 2, drug potentiation, Dose-Response Relationship, Drug, animal model, human cell, Gene Amplification, protein tyrosine kinase, azd 8055, ALK, Drug Resistance, Neoplasm, Multiprotein Complexes, Mutation, protein kinase B, Phosphatidylinositol 3-Kinase
drug megadose, mTOR inhibitor, Mice, SCID, 2 morpholino 8 phenylchromone, gedatolisib, Neuroblastoma, nuclear protein, Mice, Inbred NOD, MYCN, Antineoplastic Combined Chemotherapy Protocols, multiprotein complex, Anaplastic Lymphoma Kinase, phosphatidylinositol 3 kinase, gene mutation, Molecular Targeted Therapy, pyrazole derivative, antineoplastic agent, Oncogene Proteins, N-Myc Proto-Oncogene Protein, protein kinase inhibitor, drug cytotoxicity, target of rapamycin kinase, Nuclear Proteins, anaplastic lymphoma kinase, MTOR protein, unclassified drug, mechanistic target of rapamycin complex 1, enzyme activity, oncoprotein, MYCN gene, molecularly targeted therapy, down regulation, drug potency, pictilisib, 570, animal experiment, 610, pyridine derivative, antineoplastic activity, Mechanistic Target of Rapamycin Complex 1, Article, multiple cycle treatment, neuroblastoma, MYCN protein, Crizotinib, Cell Line, Tumor, protein S6, gene expression profiling, Animals, Humans, dactolisib, controlled study, human, ALK gene, mouse, crizotinib, mammalian target of rapamycin inhibitor, nonhuman, torin 2, drug potentiation, Dose-Response Relationship, Drug, animal model, human cell, Gene Amplification, protein tyrosine kinase, azd 8055, ALK, Drug Resistance, Neoplasm, Multiprotein Complexes, Mutation, protein kinase B, Phosphatidylinositol 3-Kinase
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