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Tumour Biol
2014 Oct 01;3510:9759-67. doi: 10.1007/s13277-014-2252-y.
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Blocking the PI3K pathway enhances the efficacy of ALK-targeted therapy in EML4-ALK-positive nonsmall-cell lung cancer.
Yang L
,
Li G
,
Zhao L
,
Pan F
,
Qiang J
,
Han S
.
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Targeted therapy based on ALK tyrosine kinase inhibitors (ALK-TKIs) has made significant achievements in individuals with EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene) fusion positive nonsmall-cell lung cancer (NSCLC). However, a high fraction of patients receive inferior clinical response to such treatment in the initial therapy, and the exact mechanisms underlying this process need to be further investigated. In this study, we revealed a persistently activated PI3K/AKT signaling that mediates the drug ineffectiveness. We found that genetic or pharmacological inhibition of ALK markedly abrogated phosphorylated STAT3 and ERK, but it failed to suppress AKT activity or induce apoptosis, in EML4-ALK-positive H2228 cells. Furthermore, targeted RNA interference of PI3K pathway components restored sensitivity to TAE684 treatment at least partially due to increased apoptosis. Combined TAE684 with PI3K inhibitor synergistically inhibited the proliferation of EML4-ALK-positive cells in vitro and significantly suppressed the growth of H2228 xenografts in vivo, suggesting the potential clinical application of such combinatorial therapy regimens in patients with EML4-ALK positive lung cancer.
Amin,
Pathobiology of ALK+ anaplastic large-cell lymphoma.
2007, Pubmed
Amin,
Pathobiology of ALK+ anaplastic large-cell lymphoma.
2007,
Pubmed
Camidge,
Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.
2012,
Pubmed
Chiarle,
The anaplastic lymphoma kinase in the pathogenesis of cancer.
2008,
Pubmed
Chou,
Drug combination studies and their synergy quantification using the Chou-Talalay method.
2010,
Pubmed
Chou,
Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors.
1984,
Pubmed
Christensen,
Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma.
2007,
Pubmed
Dai,
Incidence and patterns of ALK FISH abnormalities seen in a large unselected series of lung carcinomas.
2012,
Pubmed
Ding,
Inhibition of PI3K/mTOR overcomes nilotinib resistance in BCR-ABL1 positive leukemia cells through translational down-regulation of MDM2.
2013,
Pubmed
Doebele,
Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer.
2012,
Pubmed
Donev,
Transient PI3K inhibition induces apoptosis and overcomes HGF-mediated resistance to EGFR-TKIs in EGFR mutant lung cancer.
2011,
Pubmed
Galkin,
Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK.
2007,
Pubmed
Horn,
EML4-ALK: honing in on a new target in non-small-cell lung cancer.
2009,
Pubmed
Hynes,
PI3K inhibition overcomes trastuzumab resistance: blockade of ErbB2/ErbB3 is not always enough.
2009,
Pubmed
Iwahara,
Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system.
1997,
Pubmed
Kanaji,
Detection of EML4-ALK fusion genes in a few cancer cells from transbronchial cytological specimens utilizing immediate cytology during bronchoscopy.
2012,
Pubmed
,
Echinobase
Katayama,
Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers.
2012,
Pubmed
Koivunen,
EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer.
2008,
Pubmed
Kwak,
Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.
2010,
Pubmed
Li,
Evaluation of EML4-ALK fusion proteins in non-small cell lung cancer using small molecule inhibitors.
2011,
Pubmed
,
Echinobase
McDermott,
Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors.
2008,
Pubmed
Morris,
Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma.
1995,
Pubmed
Murugan,
Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene.
2011,
Pubmed
Ogawa,
Oncogenic mutations of ALK in neuroblastoma.
2011,
Pubmed
Popat,
Lung adenocarcinoma with concurrent exon 19 EGFR mutation and ALK rearrangement responding to erlotinib.
2011,
Pubmed
Rikova,
Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.
2007,
Pubmed
Rodon,
Development of PI3K inhibitors: lessons learned from early clinical trials.
2013,
Pubmed
Schulte,
High ALK receptor tyrosine kinase expression supersedes ALK mutation as a determining factor of an unfavorable phenotype in primary neuroblastoma.
2011,
Pubmed
Soda,
Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.
2007,
Pubmed
,
Echinobase
Tanizaki,
Combined effect of ALK and MEK inhibitors in EML4-ALK-positive non-small-cell lung cancer cells.
2012,
Pubmed
,
Echinobase
Voena,
The EGFR family members sustain the neoplastic phenotype of ALK+ lung adenocarcinoma via EGR1.
2013,
Pubmed