Reference Detail

Ref Type

Journal Article

PMID

(33166721)

Authors

Furuta H, Araki M, Masago K, Sagae Y, Fujita S, Seto K, Shimizu J, Horio Y, Sasaki E, Hosoda W, Katayama R, Okuno Y, Hida T

Title

Novel Resistance Mechanisms Including L1196Q, P1094H, and R1248_D1249 Insertion in Three Patients With NSCLC After ALK Tyrosine Kinase Inhibitor Treatment.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer	16	3	2021 Mar	477-482	J Thorac Oncol

URL

Abstract Text

The purposes of this study are to clarify the details of the ALK tyrosine kinase inhibitor (TKI) resistance mechanism in rebiopsy cases and to predict novel resistance gene alterations using molecular dynamics simulation.A total of 21 patients with ALK-positive NSCLC who underwent a rebiopsy after ALK TKI failure were included in this analysis. ALK fluorescence in situ hybridization and reverse transcription polymerase chain reaction were performed with paired initial and rebiopsy tumor specimens.Nine patients had no known ALK resistance mechanisms. Four had ALK amplification. L1196M, I1171N, and G1269A, mutations that are known to indicate resistance to ALK TKIs, were detected in one patient each. Small cell carcinoma and sarcomatoid transition were found in one case each. L1196Q, P1094H, and exon 24 76-base pair insertion were detected after the second-generation ALK TKIs.The combination of a genetic analysis and a computational simulation model may make a prediction of resistance mechanisms for overcoming ALK TKI resistance, and the construction of a genomic and simulation fused database is important for the development of personalized medicine in this field.

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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	P1094H	missense	unknown	ALK P1094H lies within the cytoplasmic domain of the Alk protein (UniProt.org). P1094H has been identified in the scientific literature (PMID: 33166721), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Jul 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
EML4 - ALK ALK G1269A	lung non-small cell carcinoma	resistant	Crizotinib	Case Reports/Case Series	Actionable	In a clinical case study, ALK G1269A was identified in the post-progression biopsy of a patient with non-small cell lung cancer harboring EML4-ALK who was treated with Xalkori (crizotinib) (PMID: 33166721).	33166721
EML4 - ALK ALK P1094H	lung non-small cell carcinoma	predicted - resistant	Alectinib	Case Reports/Case Series	Actionable	In a clinical case study, ALK P1094H was identified in the post-progression biopsy of a patient with non-small cell lung cancer harboring EML4-ALK who was treated with Alecensa (alectinib) (PMID: 33166721).	33166721
EML4 - ALK ALK I1171N	lung non-small cell carcinoma	predicted - resistant	Alectinib	Case Reports/Case Series	Actionable	In a clinical case study, ALK I1171N was identified in the post-progression biopsy of a patient with non-small cell lung cancer harboring EML4-ALK who was treated with Alecensa (alectinib) (PMID: 33166721).	33166721
EML4 - ALK ALK L1196Q	lung non-small cell carcinoma	predicted - resistant	Ceritinib	Case Reports/Case Series	Actionable	In a clinical case study, ALK L1196Q was identified in the post-progression biopsy of a patient with non-small cell lung cancer harboring EML4-ALK who was treated with Zykadia (ceritinib) (PMID: 33166721).	33166721