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Ref Type Journal Article
PMID (21838707)
Authors Schonherr C, Ruuth K, Yamazaki Y, Eriksson T, Christensen J, Palmer RH, Hallberg B
Title Activating ALK mutations found in neuroblastoma are inhibited by Crizotinib and NVP-TAE684.
Journal The Biochemical journal
Vol 440
Issue 3
Date 2011 Dec 15
URL
Abstract Text Mutations in the kinase domain of ALK (anaplastic lymphoma kinase) have recently been shown to be important for the progression of the childhood tumour neuroblastoma. In the present study we investigate six of the putative reported constitutively active ALK mutations, in positions G1128A, I1171N, F1174L, R1192P, F1245C and R1275Q. Our analyses were performed in cell-culture-based systems with both mouse and human ALK mutant variants and subsequently in a Drosophila melanogaster model system. Our investigation addressed the transforming potential of the putative gain-of-function ALK mutations as well as their signalling potential and the ability of two ATP-competitive inhibitors, Crizotinib (PF-02341066) and NVP-TAE684, to abrogate the activity of ALK. The results of the present study indicate that all mutations tested are of an activating nature and thus are implicated in tumour initiation or progression of neuroblastoma. Importantly for neuroblastoma patients, all ALK mutations used in the present study can be blocked by the inhibitors, although some mutants exhibited higher levels of drug sensitivity than others.

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Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ALK F1245C missense gain of function ALK F1245C lies within the protein kinase domain of the Alk protein (UniProt.org). F1245C results in increased downstream signaling and is transforming in cell culture (PMID: 21838707, PMID: 25517749). Y
ALK G1128A missense gain of function ALK G1128A lies within the protein kinase domain of the Alk protein (UniProt.org). G1128A confers a gain of function to the Alk protein as demonstrated by increased activation in in vitro assays (PMID: 21838707, PMID: 33674381, PMID: 25517749) and transformation in cultured cells (PMID: 21838707, PMID: 33674381, PMID: 25517749).
ALK I1171N missense gain of function ALK I1171N lies within the protein kinase domain of the Alk protein (UniProt.org). I1171N results in increased ligand-independent Alk phosphorylation and activation of the Stat pathway in culture (PMID: 23239810, PMID: 21838707), activation in in vitro assays (PMID: 33674381, PMID: 25517749), is transforming in cell culture (PMID: 23239810, (PMID: 33674381, PMID: 25517749), and has been demonstrated to occur as a secondary resistance mutation in the context of ALK fusions (PMID: 27565911). Y
ALK R1192P missense gain of function ALK R1192P lies within the protein kinase domain of the Alk protein (UniProt.org). R1192P confers a gain of function to the Alk protein as demonstrated by increased downstream signalling (PMID: 21838707), activation in in vitro assays (PMID: 33674381, PMID: 25517749), and transformation of cultured cells (PMID: 21838707, PMID: 33674381, PMID: 25517749).
ALK R1275Q missense gain of function ALK R1275Q lies within the protein kinase domain of the Alk protein (UniProt.org). R1275Q confers a gain of function to the Alk protein as demonstrated by transformation activity in cell culture and increased downstream signalling in in vitro assays (PMID: 21838707, PMID: 29533785).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References