Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK

Galkin, Anna; Melnick, Jonathan S.; Kim, Sung-Joon; Hood, Tami; Li, Nanxin; Li, Lintong; Xia, Gang; Steensma, Ruo W.; Chopiuk, Greg; Jiang, Jiaoyang; Wan, Yufeng; Ding, Peter; Liu, Yi; Sun, Fangxian; Schultz, Peter G.; Gray, Nathanael S.; Warmuth, Markus

doi:10.1073/pnas.0609412103

Cited by 334 publications

(347 citation statements)

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“…The exceptional potency of GSK1838705A in ALCL and NSCLC cell lines containing ALK fusion genes and the complete regression of NPM-ALK-dependent tumors in mice with GSK1838705A are encouraging findings for the treatment of cancers driven by oncogenic ALK. These data are consistent with the antiproliferative effects of other ALK kinase inhibitors observed in tumor cell lines harboring ALK fusion genes (18,42,46). In summary, we have shown that GSK1838705A is a potent and selective modulator of IGF-IR activity, with robust antitumor activity in animal xenograft models.…”

Section: Discussionsupporting

confidence: 76%

“…Proliferation of ALCL cell lines expressing the nucleophosmin (NPM)-ALK fusion (18,19) was inhibited by GSK1838705A in a concentration-dependent manner (EC 50 s 24-88 nmol/L; Supplementary Fig. S7A; Table 2), whereas FE-PD ALCL cells lacking the fusion (18) were relatively insensitive, with an EC 50 of 4.4 μmol/L (Supplementary Fig.…”

Section: Effect Of Igf-1r/ir Inhibition On Blood Glucose Levelsmentioning

confidence: 99%

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GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers

Sabbatini

Korenchuk

Rowand

et al. 2009

Molecular Cancer Therapeutics

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Section: Discussionsupporting

confidence: 76%

Section: Effect Of Igf-1r/ir Inhibition On Blood Glucose Levelsmentioning

confidence: 99%

GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers

Sabbatini

Korenchuk

Rowand

et al. 2009

Molecular Cancer Therapeutics

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“…Crizotinib is a small ALK and c-Met specific inhibitor, which has shown promising results in clinical trials for non-small-cell lung cancer and IMT patients. 26 --32 NVP-TAE684 is a highly specific inhibitor for ALK, 33 and was employed as a complementary inhibitor in these studies. Recently Li et al 34 compared the efficacy of crizotinib with NVP-TAE684 in a NSCLC model and demonstrated that NVP-TAE684 is more potent than crizotinib in inhibiting EML4-ALK oncogenic functions in vitro and in vivo, However, NVP-TAE684 is not currently in clinical trial.…”

Section: Resultsmentioning

confidence: 99%

Anaplastic Lymphoma Kinase (ALK) regulates initiation of transcription of MYCN in neuroblastoma cells

et al. 2012

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Neuroblastoma is a neural crest-derived embryonal tumour of the postganglionic sympathetic nervous system and a disease with several different chromosomal gains and losses, which include MYCN-amplified neuroblastoma on chromosome 2, deletions of parts of the chromosomes 1p and 11q, gain of parts of 17q and triploidy. Recently, activating mutations of the ALK (Anaplastic Lymphoma Kinase) RTK (Receptor Tyrosine Kinase) gene have been described in neuroblastoma. A meta-analysis of neuroblastoma cases revealed that ALK mutations (49 of 709 cases) in relation to genomic subtype were most frequently observed in MYCN amplified tumours (8.9%), correlating with a poor clinical outcome. MYCN proteins target proliferation and apoptotic pathways, and have an important role in the progression of neuroblastoma. Here, we show that both wild-type and gain-of-function mutants in ALK are able to stimulate transcription at the MYCN promoter and initiate mRNA transcription of the MYCN gene in both neuronal and neuroblastoma cell lines. Further, this stimulation of MYCN gene transcription and de novo MYCN protein expression is abrogated by specific ALK inhibitors, such as crizotinib (PF-2341066), NVP-TAE684, and by small interfering RNA to ALK resulting in a decrease in proliferation rate. Finally, co-transfection of ALK gain-of-function mutations together with MYCN leads to an increase in transformation potential. Taken together, our results indicate that ALK signalling regulates initiation of transcription of the MYCN gene providing a possible explanation for the poor clinical outcome observed when MYCN is amplified together with activated ALK.Oncogene (2012) 31, 5193 --5200; doi:10.1038/onc.2012.12; published online 30 January 2012Keywords: neuroblastoma; anaplastic lymphoma kinase; ALK; MYCN; transcription factor INTRODUCTION Neuroblastoma is a neural crest-derived embryonal tumour of the postganglionic sympathetic nervous system and accounts for B15% of all deaths due to paediatric tumours. 1,2 Genetically, many cases of neuroblastoma show amplification of the MYCN gene (B24% of all cases), deletions of parts of the chromosomes 1p and 11q, gain of parts of 17q and triploidy. 1,3 --6 Anaplastic Lymphoma Kinase (ALK) Receptor Tyrosine Kinase (RTK) is mutated in both familial and somatic neuroblastoma. 7 --11 Moreover, these reports also indicated that downregulation or inhibition of ALK led to a marked decrease of cell proliferation, suggesting ALK as a critical factor in the initiation and progression of neuroblastoma. The ALK RTK was first described in the mid-nineties and aberrant ALK protein activity is now implicated in a range of nonhematopoietic, hematopoietic as well as neuroendocrine tumours (for a review see Palmer et al. 12 ). A recent meta-analysis of neuroblastoma has reported ALK gain-of-function mutations to be present at a frequency of 6.9% of investigated neuroblastoma tumours. Further, a comparison of the ALK mutation frequency in relation to genomic subtype revealed that ALK mutations were most frequently obs...

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“…The presence of EML-ALK fusion in NSCLC was confirmed in a number of subsequent studies (14)(15)(16)(17)(18); however, it has not yet been detected in other carcinomas, including breast and colorectal (19,20). A number of EML4-ALK fusion variants have been identified up to date (12,18,(20)(21)(22)(23); all of them involve an almost identical portion of ALK (exons [20][21][22][23][24][25][26][27][28][29] The constitutive kinase activity of ALK is essential for proliferation of ALCL cells and its inactivation represents a feasible therapeutic approach for the treatment of ALCL (24). The intact ALK kinase domain within EML4-ALK possesses marked transforming as well as oncogenic activity in vitro and in vivo, respectively (12,21,25).…”

Section: Introductionmentioning

confidence: 88%

Exon Array Profiling Detects EML4-ALK Fusion in Breast, Colorectal, and Non–Small Cell Lung Cancers

Lin¹,

Li²,

Guan³

et al. 2009

Molecular Cancer Research

275

190

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The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene has been identified as an oncogene in a subset of non-small cell lung cancers (NSCLC). We used profiling of cancer genomes on an exon array to develop a novel computational method for the global search of gene rearrangements. This approach led to the detection of EML4-ALK fusion in breast and colorectal carcinomas in addition to NSCLC. Screening of a large collection of patient tumor samples showed the presence of EML4-ALK fusion in 2.4% of breast (5 of 209), 2.4% of colorectal (2 of 83), and in 11.3% of NSCLC (12 of 106). Besides previously known EML4-ALK variants 1 (E13; A20) and 2 (E20; A20), a novel variant E21; A20 was found in colorectal carcinoma. The presence of an EML-ALK rearrangement was verified by identifying genomic fusion points in tumor samples representative of breast, colon, and NSCLC. EML4-ALK translocation was also confirmed by fluorescence in situ hybridization assay, which revealed its substantial heterogeneity in both primary tumors and tumor-derived cell lines. To elucidate the functional significance of EML4-ALK, we examined the growth of cell lines harboring the fusion following EML4 and ALK silencing by small interfering RNA. Significant growth inhibition was observed in some but not all cell lines, suggesting their variable dependence on ALK-mediated cell survival signaling. Collectively, these findings show the recurrence of EML4-ALK fusion in multiple solid tumors and further substantiate its role in tumorigenesis. (Mol Cancer Res 2009;7(9):1466-76)

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Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK

Cited by 334 publications

References 30 publications

GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers

GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers

Anaplastic Lymphoma Kinase (ALK) regulates initiation of transcription of MYCN in neuroblastoma cells

Exon Array Profiling Detects EML4-ALK Fusion in Breast, Colorectal, and Non–Small Cell Lung Cancers

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