Gene Variant Detail

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Gene ALK
Variant C1237Y
Impact List missense
Protein Effect gain of function - predicted
Gene Variant Descriptions ALK C1237Y lies within the protein kinase domain of the Alk protein (UniProt.org). C1237Y results in both increased phosphorylation of Alk and proliferation, and has been demonstrated to confer resistance to Alk inhibitors in the context of EML4-ALK in culture (PMID: 38448512), and therefore, is predicted to lead to a gain of Alk protein function.
Associated Drug Resistance Y
Category Variants Paths

ALK mutant ALK act mut ALK C1237Y

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Transcript NM_004304.5
gDNA chr2:g.29214017C>T
cDNA c.3710G>A
Protein p.C1237Y
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_004304.5 chr2:g.29214017C>T c.3710G>A p.C1237Y RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK act mut neuroblastoma sensitive Cyclophosphamide + Lorlatinib + Topotecan Phase I Actionable In a Phase I trial, the combination of Lorbrena (lorlatinib), Topotecan, and Cytoxan (cyclophosphamide) treatment was well tolerated and resulted in a modified response rate of 63% (5/8) in pediatric patients with neuroblastoma harboring an ALK activating mutation, including ALK F1174C, F1174L, R1275Q, or R1275L (PMID: 37012551; NCT03107988). 37012551
ALK act mut neuroblastoma predicted - sensitive S63845 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, the addition of Mekinist (trametinib) sensitized a neuroblastoma cell line harboring an ALK activating mutation to S63845 (MIK655), resulting in reduced cell viability in culture (PMID: 36895472). 36895472
ALK act mut neuroblastoma predicted - sensitive Trametinib + Venetoclax Preclinical - Cell culture Actionable In a preclinical study, the addition of Mekinist (trametinib) sensitized a neuroblastoma cell line harboring an ALK activating mutation to Venclexta (venetoclax), resulting in reduced cell viability in culture (PMID: 36895472). 36895472
ALK act mut neuroblastoma sensitive Lorlatinib Phase I Actionable In a Phase I trial, Lorbrena (lorlatinib) treatment was well tolerated and resulted in a modified response rate of 30% (7/23) in children and 67% (10/15) in adults with neuroblastoma harboring an ALK activating mutation, including ALK F1174C, F1174L, R1275Q, or R1275L, F1245Y, F1245L, D1276_R1279delinsE, or amplification (PMID: 37012551; NCT03107988). 37012551
ALK act mut neuroblastoma predicted - sensitive Navitoclax + Trametinib Preclinical - Cell culture Actionable In a preclinical study, the addition of Mekinist (trametinib) sensitized neuroblastoma cell lines harboring ALK activating mutations to Navitoclax (ABT-263), resulting in reduced cell viability in culture (PMID: 36895472). 36895472
ALK act mut neuroblastoma predicted - sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NUV-655 inhibited proliferation of neuroblastoma cell lines harboring activating mutations in ALK in culture (Cancer Res (2022) 82 (12_Supplement): 3337). detail...
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...