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Gene ALK
Variant L1196M
Impact List missense
Protein Effect gain of function
Gene Variant Descriptions ALK L1196M lies within the protein kinase domain of the Alk protein (UniProt.org). L1196M results in increased Alk kinase activity (PMID: 30258533), modest Alk autophosphorylation, and transformation in cell culture (PMID: 25517749), and confers resistance to Alk inhibitors in the context of ALK rearrangements in culture and in vivo (PMID: 21613408, PMID: 25421750, PMID: 31452835).
Associated Drug Resistance Y
Category Variants Paths

ALK mutant ALK act mut ALK L1196M

ALK mutant ALK L1196X ALK L1196M

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Transcript NM_004304.5
gDNA chr2:g.29220765G>T
cDNA c.3586C>A
Protein p.L1196M
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_004304 chr2:g.29220765G>T c.3586C>A p.L1196M RefSeq GRCh38/hg38
NM_004304.5 chr2:g.29220765G>T c.3586C>A p.L1196M RefSeq GRCh38/hg38
NM_004304.4 chr2:g.29220765G>T c.3586C>A p.L1196M RefSeq GRCh38/hg38

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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...
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 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 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 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 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