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Ref Type Journal Article
PMID (36201110)
Authors Doi Y, Tagaya H, Noge A, Semba K
Title Prediction of Resistance Mutations Against Upcoming Anaplastic Lymphoma Kinase Inhibitors.
Journal Vol Issue Date Pages Journal Short Title
Targeted oncology 2022 Oct 06 695-707 Target Oncol
URL
Abstract Text Chromosomal aberrations involving the anaplastic lymphoma kinase (ALK) gene have been observed in approximately 4% of patients with non-small cell lung cancer (NSCLC). Although these patients clinically benefit from treatment with various ALK tyrosine kinase inhibitors (ALK-TKIs), none of these can inhibit the development of resistance mutations. Considering inevitable drug resistance and the variety of available ALK-TKIs, it is necessary to predict the pattern of drug-resistance mutations to determine the optimal treatment strategy.We aimed to establish a polymerase chain reaction (PCR)-based system to predict the development of resistance mutations against ALK-TKIs and identify therapeutic strategies using the upcoming ALK-TKIs repotrectinib (TPX-0005) and ensartinib (X-396) following recurrence on first-line alectinib treatment for ALK-positive NSCLC.An error-prone PCR-based method for predicting drug resistance mutations was established and the half-maximal inhibitory concentration (IC50) values of the predicted ALK mutations were evaluated in a Ba/F3 cell-based assay.We predicted several resistance mutations against repotrectinib and ensartinib, and demonstrated that the next-generation ALK-TKI TPX-0131, was active against repotrectinib-resistant mutations and that the FLT3 inhibitor gilteritinib was active against ensartinib-resistant mutations.We developed a PCR-based system for predicting drug resistance mutations. When this system was applied to repotrectinib and ensartinib, the results suggested that these drugs can be used for the second-line treatment of ALK-positive NSCLC. Predicting resistance mutations against TKIs will provide useful information to aid in the development of effective therapeutic strategies.

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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 F1174I ALK G1202R Advanced Solid Tumor resistant TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R and F1174I were resistant to TPX-0131 in culture (PMID: 36201110). 36201110
EML4 - ALK ALK C1156Y ALK G1202R Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R and C1156Y were resistant to Xalkori (crizotinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK I1171N ALK L1256F Advanced Solid Tumor sensitive Alectinib Preclinical - Cell culture Actionable In a preclinical study, Alecensa (alectinib) treatment inhibited Alk phosphorylation and viability of transformed cells expressing EML4-ALK with ALK I1171N and L1256F in culture (PMID: 36201110). 36201110
EML4 - ALK ALK C1156Y ALK I1171N Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171N and C1156Y were resistant to Alecensa (alectinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK C1156Y ALK G1202R Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R and C1156Y were resistant to Lorbrena (lorlatinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK C1156Y ALK I1171N Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171N and C1156Y were resistant to Lorbrena (lorlatinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK G1202R Advanced Solid Tumor resistant Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R were resistant to Xospata (gilteritinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK E1129V ALK G1202R Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R and E1129V were resistant to Alecensa (alectinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK G1202R Advanced Solid Tumor sensitive Repotrectinib Preclinical - Cell culture Actionable In a preclinical study, Augtyro (repotrectinib) inhibited Alk phosphorylation and viability of transformed cells expressing EML4-ALK with ALK G1202R in culture (PMID: 36201110). 36201110
EML4 - ALK ALK C1156Y ALK G1202R Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R and C1156Y were resistant to Alecensa (alectinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK E1129V ALK I1171N Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171N and E1129V were resistant to Xalkori (crizotinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK C1156Y ALK G1202R Advanced Solid Tumor sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R and C1156Y were resistant to Xospata (gilteritinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK E1129V ALK I1171N Advanced Solid Tumor resistant TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171N and E1129V were resistant to TPX-0131 in culture (PMID: 36201110). 36201110
EML4 - ALK ALK C1156Y ALK I1171N Advanced Solid Tumor resistant TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171N and C1156Y were resistant to TPX-0131 in culture (PMID: 36201110). 36201110
EML4 - ALK ALK C1156Y ALK I1171N Advanced Solid Tumor sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) treatment inhibited Alk phosphorylation and viability of transformed cells expressing EML4-ALK with ALK I1171N and C1156Y in culture (PMID: 36201110). 36201110
EML4 - ALK ALK I1171N Advanced Solid Tumor sensitive Ensartinib Preclinical - Cell culture Actionable In a preclinical study, Ensacove (ensartinib) inhibited Alk phosphorylation and viability of transformed cells expressing EML4-ALK with ALK I1171N in culture (PMID: 36201110). 36201110
EML4 - ALK ALK I1171N ALK L1256F Advanced Solid Tumor resistant TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171N and L1256F were resistant to TPX-0131 in culture (PMID: 36201110). 36201110
EML4 - ALK ALK L1196M ALK G1202R Advanced Solid Tumor resistant Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R and L1196M were resistant to Xospata (gilteritinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK I1171N ALK L1256F Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171N and L1256F were resistant to Lorbrena (lorlatinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK E1129V ALK I1171N Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171N and E1129V were resistant to Lorbrena (lorlatinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK F1174I ALK G1202R Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R and F1174I were resistant to Lorbrena (lorlatinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK I1171N Advanced Solid Tumor resistant TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171N were resistant to TPX-0131 in culture (PMID: 36201110). 36201110
EML4 - ALK ALK C1156Y ALK G1202R Advanced Solid Tumor sensitive TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, TPX-0131 treatment inhibited Alk phosphorylation and viability of transformed cells expressing EML4-ALK with ALK G1202R and C1156Y in culture (PMID: 36201110). 36201110
EML4 - ALK ALK G1202R Advanced Solid Tumor resistant Ensartinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R were resistant to Ensacove (ensartinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK F1174C ALK G1202R Advanced Solid Tumor resistant TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R and F1174C were resistant to TPX-0131 in culture (PMID: 36201110). 36201110
EML4 - ALK ALK I1171N ALK L1256F Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171N and L1256F were resistant to Xalkori (crizotinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK E1129V ALK I1171N Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171N and E1129V were resistant to Alecensa (alectinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK F1174I ALK G1202R Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R and F1174I were resistant to Xalkori (crizotinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK L1196M ALK G1202R Advanced Solid Tumor sensitive TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, TPX-0131 treatment inhibited Alk phosphorylation and viability of transformed cells expressing EML4-ALK with ALK G1202R and L1196M in culture (PMID: 36201110). 36201110
EML4 - ALK ALK F1174I ALK G1202R Advanced Solid Tumor resistant Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R and F1174I were resistant to Xospata (gilteritinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK I1171N ALK L1256F Advanced Solid Tumor sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) treatment inhibited Alk phosphorylation and viability of transformed cells expressing EML4-ALK with ALK I1171N and L1256F in culture (PMID: 36201110). 36201110
EML4 - ALK ALK L1196M ALK G1202R Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R and L1196M were resistant to Lorbrena (lorlatinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK F1174C ALK G1202R Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R and F1174C were resistant to Xalkori (crizotinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK I1171N Advanced Solid Tumor resistant Repotrectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171N were resistant to Augtyro (repotrectinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK E1129V ALK G1202R Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R and E1129V were resistant to Lorbrena (lorlatinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK G1202R Advanced Solid Tumor sensitive TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, TPX-0131 treatment inhibited Alk phosphorylation and viability of transformed cells expressing EML4-ALK with ALK G1202R in culture (PMID: 36201110). 36201110
EML4 - ALK ALK F1174C ALK G1202R Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R and F1174C were resistant to Lorbrena (lorlatinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK F1174C ALK G1202R Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R and F1174C were resistant to Alecensa (alectinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK E1129V ALK G1202R Advanced Solid Tumor resistant Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R and E1129V were resistant to Xospata (gilteritinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK L1196M ALK G1202R Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R and L1196M were resistant to Xalkori (crizotinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK F1174I ALK G1202R Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R and F1174I were resistant to Alecensa (alectinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK F1174C ALK G1202R Advanced Solid Tumor resistant Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R and F1174C were resistant to Xospata (gilteritinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK E1129V ALK G1202R Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R and E1129V were resistant to Xalkori (crizotinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK C1156Y ALK I1171N Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171N and C1156Y were resistant to Xalkori (crizotinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK L1196M ALK G1202R Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R and L1196M were resistant to Alecensa (alectinib) in culture (PMID: 36201110). 36201110
EML4 - ALK ALK E1129V ALK G1202R Advanced Solid Tumor sensitive TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, TPX-0131 treatment inhibited Alk phosphorylation and viability of transformed cells expressing EML4-ALK with ALK G1202R and E1129V in culture (PMID: 36201110). 36201110