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Ref Type Journal Article
PMID (27565908)
Authors Lucena-Araujo AR, Moran JP, VanderLaan PA, Dias-Santagata D, Folch E, Majid A, Kent MS, Gangadharan SP, Rangachari D, Huberman MS, Kobayashi SS, Costa DB
Title De novo ALK kinase domain mutations are uncommon in kinase inhibitor-naïve ALK rearranged lung cancers.
Abstract Text Anaplastic lymphoma kinase (ALK) rearranged lung adenocarcinomas are responsive to the multitargeted ALK inhibitor crizotinib. One of the common mechanisms of resistance to crizotinib is the acquisition of ALK kinase domain mutations. However, the presence of ALK mutations in crizotinib-naïve tumors has not been widely reported and it is unclear if de novo ALK mutations affect the response to crizotinib.We analyzed preclinical models of ALK rearranged lung cancers that were sensitive/resistant to ALK inhibitors, probed our institutional and other lung cancer databases for tumors with ALK kinase domain mutations, and evaluated tumor response to crizotinib.ALK rearranged cell lines with ALK kinase domain mutations were heterogeneously less inhibited by increasing concentrations of crizotinib than cells driven solely by EML4-ALK fusions. Previous ALK rearranged lung cancer cohorts did not report ALK kinase mutations in inhibitor-naïve tumors. We identified one TKI-naïve ALK rearranged tumor with an ALK kinase domain mutation: ALK-S1206F (mutations at ALK-S1206 shifted crizotinib inhibitory curves only minimally in preclinical models). The never smoker whose tumor harbored de novo EML4-ALK-E5;A20+ALK-S1206F only achieved a 4-month radiographic response to crizotinib 250mg twice daily.Combining data from our and prior cohorts, ALK kinase domain mutations were uncommon events (<3% of cases) in ALK inhibitor-naïve ALK rearranged lung adenocarcinomas but their effect on intrinsic resistance to ALK inhibitors should be better evaluated.


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Molecular Profile Treatment Approach
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 S1206F missense unknown ALK S1206F lies within the protein kinase domain of the Alk protein ( S1206F has been identified in the scientific literature (PMID: 27565908, PMID: 31712133, PMID: 34589977), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Dec 2023).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4 - ALK ALK S1206F lung adenocarcinoma predicted - sensitive Crizotinib Case Reports/Case Series Actionable In a clinical case study, Xalkori (crizotinib) treatment resulted in clinical improvement within one week of therapy, a 30.3% decrease in target lesion and a partial response after 2 months, and an ongoing response after 4 months in a patient with lung adenocarcinoma harboring de novo EML4-ALK-(E5;A20) and ALK S1206F (PMID: 27565908). 27565908