Reference Detail

Ref Type

Journal Article

PMID

(31943796)

Authors

Takahashi K, Seto Y, Okada K, Uematsu S, Uchibori K, Tsukahara M, Oh-Hara T, Fujita N, Yanagitani N, Nishio M, Okubo K, Katayama R

Title

Overcoming resistance by ALK compound mutation (I1171S + G1269A) after sequential treatment of multiple ALK inhibitors in non-small cell lung cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Thoracic cancer	11	3	2020 Mar	581-587	Thorac Cancer

URL

Abstract Text

Anaplastic lymphoma kinase (ALK) fusion genes are found in 3%-5% of non-small cell lung cancers (NSCLCs). ALK inhibitors show a very high response rate to ALK-positive NSCLCs. However, the emergence of acquired resistance is inevitable. In this study, we investigated the drugs for overcoming resistance especially compound mutations after sequential treatment with crizotinib, alectinib, and lorlatinib.Next-generation sequencing (NGS) and Sanger sequencing were performed on a liver biopsy tissue obtained from a clinical case. Ba/F3 cells in which mutant EML4-ALK were overexpressed were prepared, and cell viability assay and immunoblotting were performed to check the sensitivity of five independent ALK inhibitors.I1171S + G1269A double mutation was identified by NGS and Sanger sequencing on a liver biopsy tissue from a patient who relapsed on lorlatinib treatment. Ceritinib and brigatinib-but not other ALK inhibitors-were active against the compound mutations in the cell line model.With the sequential ALK inhibitors treatment, cancer cells accumulate new mutations in addition to mutations acquired previously. The identified compound mutation (I1171S + G1269A) was found to be sensitive to ceritinib and brigatinib, and indeed the patient's tumor partially responded to ceritinib.ALK compound mutation was found in a clinical sample that was resistant to lorlatinib after sequential ALK-tyrosine kinase inhibitor (TKI) treatment. Ceritinib and brigatinib are potential overcoming drugs against ALK I1171S + G1269A double mutation.

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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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
EML4 - ALK ALK I1171S	Advanced Solid Tumor	conflicting	Brigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Alunbrig (brigatinib) reduced ALK phosphorylation and inhibited growth of transformed cells expressing EML4-ALK with ALK I1171S in culture (PMID: 31943796).	31943796
EML4 - ALK ALK I1171S ALK G1269A	Advanced Solid Tumor	sensitive	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, Zykadia (ceritinib) reduced ALK phosphorylation and inhibited growth of transformed cells expressing EML4-ALK with ALK I1171S and ALK G1269A in culture (PMID: 31943796).	31943796
EML4 - ALK ALK I1171S ALK G1269A	Advanced Solid Tumor	sensitive	Brigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Alunbrig (brigatinib) reduced ALK phosphorylation and inhibited growth of transformed cells expressing EML4-ALK with ALK I1171S and ALK G1269A in culture (PMID: 31943796).	31943796
EML4 - ALK ALK I1171S ALK G1269A	Advanced Solid Tumor	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171S and ALK G1269A demonstrated resistance to Lorbrena (lorlatinib) treatment in culture (PMID: 31943796).	31943796
EML4 - ALK ALK I1171S	Advanced Solid Tumor	conflicting	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, Zykadia (ceritinib) reduced ALK phosphorylation and inhibited growth of transformed cells expressing EML4-ALK with ALK I1171S in culture (PMID: 31943796).	31943796
EML4 - ALK ALK I1171S ALK G1269A	Advanced Solid Tumor	resistant	Alectinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171S and ALK G1269A demonstrated resistance to Alecensa (alectinib) treatment in culture (PMID: 31943796).	31943796
EML4 - ALK ALK I1171S ALK G1269A	Advanced Solid Tumor	resistant	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171S and ALK G1269A demonstrated resistance to Xalkori (crizotinib) treatment in culture (PMID: 31943796).	31943796