Gene Variant Detail

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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

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Transcript NM_004304.4
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 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

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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 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 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 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 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) inhibited proliferation of neuroblastoma cells harboring ALK R1275Q in culture (PMID: 29907598). 29907598
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 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 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 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 Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorlatinib (PF-06463922) inhibited foci formation more efficiently than Xalkori (crizotinib) in transformed cells over expressing ALK R1275Q in culture (PMID: 26554404). 26554404
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 F1174L ALK R1275Q neuroblastoma predicted - sensitive 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, a patient harboring both ALK F1174V and ALK R1275Q stayed on treatment for 3 cycle until disease progression (PMID: 33568345; NCT00939770). 33568345
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK mutant lung non-small cell carcinoma no benefit Belizatinib Phase I Actionable In a Phase I trial, treatment with Belizatinib (TSR-011) in ALK inhibitor-naive non-small cell lung cancer patients (n=14) harboring either an ALK mutation, ALK amplification, or an ALK rearrangement resulted in a partial response in 6 patients and stable disease in 8 patients, however, it was determined that the drug resulted in limited efficacy and development of the drug was discontinued (PMID: 31217479; NCT02048488). 31217479
ALK mutant lung non-small cell carcinoma no benefit Crizotinib + Onalespib Phase II Actionable In a Phase II trial, Onalespib (AT13387) and Xalkori (crizotinib) combination treatment did not significantly improve median progression free survival (269 vs 266 days) or objective response rate (55.4%, 38/68 vs 45.3%, 31/68) compared to Xalkori (crizotinib) single treatment in patients with non-small cell lung carcinoma harboring either an ALK mutation or ALK rearrangement (J Clin Oncol 34, 2016 (suppl; abstr 9059); NCT01712217). detail...