A Genetically Engineered Mouse Model of Neuroblastoma Driven by Mutated ALK and MYCN
Annual rept. 1 Sep 2013 - 31 Aug 2014
DANA-FARBER CANCER INST BOSTON MA
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During year 1 of this project, we have made substantial progress in achieving the goals that were listed in the original statement of work. We have characterized the downstream signaling pathways employed by the two most common ALK mutations in neuroblastoma, F1174L and R1275Q. We have determined that in tumors cells expressing mutated ALK, different downstream signaling pathways are active depending on the presence or absence of amplified MYCN. We demonstrate that in ALKmutated, 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 ALKF1174LMYCN-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 nonamplified 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.
- Medicine and Medical Research