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Gene ALK
Variant R1275Q
Impact List missense
Protein Effect gain of function
Gene Variant Descriptions 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).
Associated Drug Resistance
Category Variants Paths

ALK mutant ALK act mut ALK R1275Q

ALK mutant ALK R1275X ALK R1275Q

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Transcript NM_004304.5
gDNA chr2:g.29209798C>T
cDNA c.3824G>A
Protein p.R1275Q
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_004304.5 chr2:g.29209798C>T c.3824G>A p.R1275Q RefSeq GRCh38/hg38
NM_004304.4 chr2:g.29209798C>T c.3824G>A p.R1275Q RefSeq GRCh38/hg38
NM_004304 chr2:g.29209798C>T c.3824G>A p.R1275Q RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK R1275Q neuroblastoma sensitive Crizotinib + Cyclophosphamide + Topotecan Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Xalkori (crizotinib), Topotecan, and Cytoxan (cyclophosphamide) synergized to sustain tumor regression in human neuroblastoma cell line xenograft models harboring ALK R1275Q and wild-type TP53 (PMID: 26438783). 26438783
ALK R1275Q Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell line xenograft Actionable In a preclinical study, a transformed cell line expressing ALK R1275Q was sensitive to Alunbrig (brigatinib) in culture and in cell line xenograft models, resulting in cell growth inhibition (PMID: 27049722). 27049722
ALK R1275Q neuroblastoma conflicting Crizotinib Case Reports/Case Series Actionable In a Phase I/II trial (ADVL0912), Xalkori (crizotinib) treatment resulted in an objective response of 15% (3/20) in pediatric patients with relapsed/refractory neuroblastoma harboring ALK activating mutations or amplifications, among the 12 patients harboring ALK R1275Q, 1 achieved a complete response, 2 achieved partial responses, and 2 achieved prolonged stable diseases (PMID: 33568345; NCT00939770). 33568345
ALK R1275Q neuroblastoma conflicting Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) decreased viability of neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 38032104). 38032104
ALK R1275Q neuroblastoma conflicting Crizotinib Preclinical - Cell line xenograft Actionable In a preclinical study, Xalkori (crizotinib) did not inhibit growth of neuroblastoma cells over expressing ALK R1275Q in culture, and only delayed tumor growth in cell line xenograft models (PMID: 26554404). 26554404
ALK R1275Q neuroblastoma conflicting Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) inhibited proliferation of neuroblastoma cells harboring ALK R1275Q in culture (PMID: 29907598). 29907598
ALK R1275Q neuroblastoma conflicting Crizotinib Preclinical Actionable In a preclinical study, Xalkori (crizotinib) treatment resulted in decreased tumor weight in a Mycn-overexpressing neuroblastoma transgenic mouse model with ALK R1275Q (corresponds to R1279Q in mouse) and subsequent upregulation of Ret (PMID: 24811913). 24811913
ALK R1275Q neuroblastoma sensitive Lorlatinib Case Reports/Case Series Actionable In a clinical case study, Lorbrena (lorlatinib) treatment resulted in a partial response in 3 of 4 patients with neuroblastoma harboring ALK R1275Q (PMID: 37561984). 37561984
ALK R1275Q neuroblastoma sensitive Lorlatinib Case Reports/Case Series Actionable In a Phase I trial, Lorbrena (lorlatinib) treatment resulted in a complete response in a neuroblastoma patient harboring a germline ALK R1275Q, who was on treatment for 18 months and remained in remission at 5 years (PMID: 37147298; NCT03107988). 37147298
ALK R1275Q neuroblastoma sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorbrena (lorlatinib) decreased viability of neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 38032104). 38032104
ALK R1275Q neuroblastoma sensitive Lorlatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Lorbrena (lorlatinib) inhibited Alk phosphorylation, resulted in growth inhibition of neuroblastoma cells over expressing ALK R1275Q in culture and induced rapid and sustained complete tumor regression in cell line xenograft models (PMID: 26554404). 26554404
ALK R1275Q Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorbrena (lorlatinib) inhibited foci formation more efficiently than Xalkori (crizotinib) in transformed cells overexpressing ALK R1275Q in culture (PMID: 26554404). 26554404
ALK R1275Q neuroblastoma sensitive CEP-28122 Preclinical - Cell culture Actionable In a preclinical study, CEP-28122 inhibited growth of neuroblastoma cells harboring ALK R1275Q in culture (PMID: 22203728). 22203728
ALK R1275Q neuroblastoma sensitive Ceritinib Case Reports/Case Series Actionable In a Phase I trial, Zykadia (ceritinib) treatment resulted in 3 partial responses and 1 stable disease in 7 pediatric patients with neuroblastoma harboring ALK R1275Q (PMID: 34780709; NCT01742286). 34780709
ALK R1275Q neuroblastoma sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) decreased viability of neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 38032104). 38032104
ALK R1275Q neuroblastoma sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) inhibited proliferation of neuroblastoma cells harboring ALK R1275Q in culture (PMID: 29907598). 29907598
ALK R1275Q neuroblastoma no benefit Belizatinib Case Reports/Case Series Actionable In a Phase I trial, a neuroblastoma patient harboring ALK R1275Q did not respond to treatment with Belizatinib (TSR-011) (PMID: 31217479; NCT02048488). 31217479
ALK R1275Q Advanced Solid Tumor predicted - sensitive TPX-0131 Preclinical - Biochemical Actionable In a preclinical study, TPX-0131 inhibited kinase activity of ALK R1275Q in an in vitro assay (PMID: 34158340). 34158340
ALK R1275Q neuroblastoma sensitive Vandetanib Preclinical Actionable In a preclinical study, Caprelsa (vandetanib) treatment resulted in decreased tumor weight in a Mycn-overexpressing neuroblastoma transgenic mouse model with ALK R1275Q (corresponds to R1279Q in mouse) and subsequent upregulation of Ret (PMID: 24811913). 24811913
ALK R1275Q Advanced Solid Tumor sensitive Repotrectinib Preclinical - Cell culture Actionable In a preclinical study, Augtyro (repotrectinib) decreased Alk phosphorylation and neurite outgrowth in cells expressing ALK R1275Q in culture (PMID: 31852910). 31852910
ALK R1275Q neuroblastoma predicted - sensitive Ensartinib Preclinical - Cell culture Actionable In a preclinical study, Ensartinib (X-396) treatment resulted in inhibition of cell proliferation in a neuroblastoma cell line harboring ALK R1275Q in culture (PMID: 34482287). 34482287
ALK R1275Q neuroblastoma predicted - sensitive Repotrectinib Preclinical - Cell culture Actionable In a preclinical study, Augtyro (repotrectinib) treatment resulted in inhibition of cell proliferation in a neuroblastoma cell line harboring ALK R1275Q in culture (PMID: 34482287). 34482287
ALK R1275Q Advanced Solid Tumor predicted - sensitive Conteltinib Preclinical - Biochemical Actionable In a preclinical study, Conteltinib (CT-707) inhibited ALK R1275Q activity in an in vitro assay (PMID: 36424628). 36424628
ALK R1275Q neuroblastoma sensitive Ceritinib + Ribociclib Preclinical - Cell culture Actionable In a preclinical study, the combination of Zykadia (ceritinib) and Kisqali (ribociclib) synergistically inhibited proliferation and Alk phosphorylation and induced cell cycle arrest in neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 27986745). 27986745
ALK R1275Q neuroblastoma sensitive TNO155 Preclinical - Cell culture Actionable In a preclinical study, TNO155 decreased viability of neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 38032104). 38032104
ALK R1275Q neuroblastoma sensitive Ceritinib + TNO155 Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of TNO155 and Zykadia (ceritinib) synergistically decreased viability of neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 38032104). 38032104
ALK R1275Q neuroblastoma sensitive Lorlatinib + TNO155 Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of TNO155 and Lorbrena (lorlatinib) synergistically decreased viability of neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 38032104). 38032104
ALK R1275Q neuroblastoma sensitive Crizotinib + TNO155 Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of TNO155 and Xalkori (crizotinib) synergistically decreased viability of neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 38032104). 38032104
ALK R1275Q neuroblastoma sensitive Crizotinib + SHP099 Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of SHP099 and Xalkori (crizotinib) synergistically decreased viability of neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 38032104). 38032104
ALK R1275Q neuroblastoma sensitive Ceritinib + SHP099 Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of SHP099 and Zykadia (ceritinib) synergistically decreased viability of neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 38032104). 38032104
ALK R1275Q neuroblastoma sensitive Lorlatinib + SHP099 Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of SHP099 and Lorbrena (lorlatinib) synergistically decreased viability of neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 38032104). 38032104
ALK R1275Q neuroblastoma sensitive SHP099 Preclinical - Cell culture Actionable In a preclinical study, SHP099 decreased viability of neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 38032104). 38032104