Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Lung cancer (Amsterdam, Netherlands)	99		2016 Sep	17-22	Lung Cancer

URL

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 (UniProt.org). 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, Aug 2024).

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