Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
The Biochemical journal	440	3	2011 Dec 15	405-13	Biochem J

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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Molecular Profile	Treatment Approach
ALK L1196M	ALK Inhibitor
ALK I1170V	ALK Inhibitor
ALK L1198P	ALK Inhibitor
ALK G1201E	ALK Inhibitor
ALK F856S	ALK Inhibitor
ALK R1192P	ALK Inhibitor
ALK T1151M	ALK Inhibitor
ALK F1174C	ALK Inhibitor
ALK I1170N	ALK Inhibitor
ALK Y1278S	ALK Inhibitor
ALK G1128A	ALK Inhibitor
ALK L1198F	ALK Inhibitor
ALK fusion	ALK Inhibitor
ALK F1245C	ALK Inhibitor
ALK L1196Q	ALK Inhibitor
ALK I1170S	ALK Inhibitor
ALK I1171N	ALK Inhibitor
ALK act mut	ALK Inhibitor
ALK G1269S	ALK Inhibitor
ALK R1275Q	ALK Inhibitor
ALK F1245V	ALK Inhibitor
ALK F1174S	ALK Inhibitor
ALK F1174L	ALK Inhibitor
ALK K1062M	ALK Inhibitor
ALK D1163N	ALK Inhibitor
ALK M1166R	ALK Inhibitor
ALK rearrange	ALK Inhibitor
ALK F1174I	ALK Inhibitor
ALK A348D	ALK Inhibitor
ALK F1174V	ALK Inhibitor

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