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Oncotarget. 2014 Sep 30;5(18):8737-49.

Molecular rationale for the use of PI3K/AKT/mTOR pathway inhibitors in combination with crizotinib in ALK-mutated neuroblastoma.

Author information

1
Departments of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA. These authors contributed equally to this work.
2
Departments of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA.
3
Broad Institute of MIT and Harvard, Cambridge, MA.
4
Cancer Biology, Dana-Farber Cancer Institute, Boston, MA. Departments of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA.
5
Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, MA.
6
Departments of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA. Cancer Science Institute of Singapore, Singapore.
7
Institute of Cancer Research, Sutton, United Kingdom.
8
Departments of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA. Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, MA.
9
Departments of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA. Broad Institute of MIT and Harvard, Cambridge, MA.

Abstract

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.

PMID:
25228590
PMCID:
PMC4226718
DOI:
10.18632/oncotarget.2372
[Indexed for MEDLINE]
Free PMC Article

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