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Ref Type Journal Article
PMID (25727400)
Authors Fontana D, Ceccon M, Gambacorti-Passerini C, Mologni L
Title Activity of second-generation ALK inhibitors against crizotinib-resistant mutants in an NPM-ALK model compared to EML4-ALK.
Journal Vol Issue Date Pages Journal Short Title
Cancer medicine 4 7 2015 Jul 953-65 Cancer Med
URL
Abstract Text Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor involved in both solid and hematological tumors. About 80% of ALK-positive anaplastic large-cell lymphoma (ALCL) cases are characterized by the t(2;5)(p23;q35) translocation, encoding for the aberrant fusion protein nucleophosmin (NPM)-ALK, whereas 5% of non-small-cell lung cancer (NSCLC) patients carry the inv(2)(p21;p23) rearrangement, encoding for the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion. The ALK/c-MET/ROS inhibitor crizotinib successfully improved the treatment of ALK-driven diseases. However, several cases of resistance appeared in NSCLC patients, and ALK amino acid substitutions were identified as a leading cause of resistance to crizotinib. Second-generation ALK inhibitors have been developed in order to overcome crizotinib resistance. In this work, we profiled in vitro the activity of crizotinib, AP26113, ASP3026, alectinib, and ceritinib against six mutated forms of ALK associated with clinical resistance to crizotinib (C1156Y, L1196M, L1152R, G1202R, G1269A, and S1206Y) and provide a classification of mutants according to their level of sensitivity/resistance to the drugs. Since the biological activity of ALK mutations extends beyond the specific type of fusion, both NPM-ALK- and EML4-ALK-positive cellular models were used. Our data revealed that most mutants may be targeted by using different inhibitors. One relevant exception is represented by the G1202R substitution, which was highly resistant to all drugs (>10-fold increased IC50 compared to wild type) and may represent the most challenging mutation to overcome. These results provide a prediction of cross-resistance of known crizotinib-resistant mutations against all second-generation tyrosine kinase inhibitors (TKIs) clinically available, and therefore could be a useful tool to help clinicians in the management of crizotinib-resistance cases.

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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 S1206Y missense unknown ALK S1206Y lies within the protein kinase domain of the Alk protein (UniProt.org). S1206Y has been demonstrated to occur as a secondary drug resistance mutation in the context of ALK rearrangements (PMID: 22277784, PMID: 24675041, PMID: 25727400), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Aug 2024). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4 - ALK ALK G1269A Advanced Solid Tumor conflicting Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1269A demonstrated resistance to Alecensa (alectinib) in culture (PMID: 25727400). 25727400
EML4 - ALK ALK G1202R Advanced Solid Tumor conflicting Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R demonstrated resistance to Alunbrig (brigatinib) in culture (PMID: 25727400). 25727400
EML4 - ALK ALK G1202R Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R demonstrated resistance to Xalkori (crizotinib) in culture (PMID: 25727400). 25727400
EML4 - ALK ALK L1152R Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK L1152R demonstrated resistance to Zykadia (ceritinib) in culture (PMID: 25727400). 25727400
EML4 - ALK ALK G1202R Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R demonstrated resistance to Zykadia (ceritinib) in culture (PMID: 25727400). 25727400
EML4 - ALK ALK L1196M Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) inhibited proliferation of transformed cells expressing EML4-ALK with ALK L1196M in culture (PMID: 25727400). 25727400
EML4 - ALK ALK L1152R Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK L1152R demonstrated resistance to Xalkori (crizotinib) in culture (PMID: 25727400). 25727400
EML4 - ALK ALK G1269A Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) inhibited proliferation of transformed cells expressing EML4-ALK with ALK G1269A in culture (PMID: 25727400). 25727400
EML4 - ALK ALK C1156Y Advanced Solid Tumor sensitive ASP3026 Preclinical - Cell culture Actionable In a preclinical study, ASP3026 inhibited proliferation of transformed cells expressing EML4-ALK with ALK C1156Y in culture (PMID: 25727400). 25727400
EML4 - ALK ALK S1206Y Advanced Solid Tumor conflicting Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK S1206Y demonstrated moderate resistance to Alunbrig (brigatinib) in culture (PMID: 25727400). 25727400
EML4 - ALK ALK C1156Y Advanced Solid Tumor sensitive Alectinib Preclinical - Cell culture Actionable In a preclinical study, Alecensa (alectinib) inhibited proliferation of transformed cells expressing EML4-ALK with ALK C1156Y in culture (PMID: 25727400). 25727400
EML4 - ALK ALK L1152R Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK L1152R demonstrated resistance to ASP3026 in culture (PMID: 25727400). 25727400
EML4 - ALK ALK G1202R Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R demonstrated resistance to Alecensa (alectinib) in culture (PMID: 25727400). 25727400
EML4 - ALK ALK L1152R Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) inhibited proliferation of transformed cells expressing EML4-ALK with ALK L1152R in culture (PMID: 25727400). 25727400
EML4 - ALK ALK L1196M Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK L1196M demonstrated resistance to Xalkori (crizotinib) in culture (PMID: 25727400). 25727400
EML4 - ALK ALK C1156Y Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK C1156Y demonstrated moderate resistance to Xalkori (crizotinib) in culture (PMID: 25727400). 25727400
EML4 - ALK ALK G1202R Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R demonstrated resistance to ASP3026 in culture (PMID: 25727400). 25727400
EML4 - ALK ALK G1269A Advanced Solid Tumor sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) inhibited proliferation of transformed cells expressing EML4-ALK with ALK G1269A in culture (PMID: 25727400). 25727400
EML4 - ALK ALK S1206Y Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK S1206Y demonstrated moderate resistance to ASP3026 in culture (PMID: 25727400). 25727400
EML4 - ALK ALK G1269A Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1269A demonstrated moderate resistance to ASP3026 in culture (PMID: 25727400). 25727400
EML4 - ALK ALK C1156Y Advanced Solid Tumor predicted - sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) inhibited proliferation of transformed cells expressing EML4-ALK with ALK C1156Y in culture (PMID: 25727400). 25727400
EML4 - ALK ALK L1196M Advanced Solid Tumor conflicting Alectinib Preclinical - Cell culture Actionable In a preclinical study, Alecensa (alectinib) inhibited proliferation of transformed cells expressing EML4-ALK with ALK L1196M in culture (PMID: 25727400). 25727400
EML4 - ALK ALK S1206Y Advanced Solid Tumor sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) inhibited proliferation of transformed cells expressing EML4-ALK with ALK S1206Y in culture (PMID: 25727400). 25727400
EML4 - ALK ALK L1196M Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK L1196M demonstrated moderate resistance to ASP3026 in culture (PMID: 25727400). 25727400
EML4 - ALK ALK L1152R Advanced Solid Tumor sensitive Alectinib Preclinical - Cell culture Actionable In a preclinical study, Alecensa (alectinib) inhibited proliferation of transformed cells expressing EML4-ALK with ALK L1152R in culture (PMID: 25727400). 25727400
EML4 - ALK ALK S1206Y Advanced Solid Tumor conflicting Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK S1206Y demonstrated moderate resistance to Alecensa (alectinib) in culture (PMID: 25727400). 25727400
EML4 - ALK ALK L1196M Advanced Solid Tumor sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) inhibited proliferation of transformed cells expressing EML4-ALK with ALK L1196M in culture (PMID: 25727400). 25727400
EML4 - ALK ALK G1269A Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1269A demonstrated resistance to Xalkori (crizotinib) in culture (PMID: 25727400). 25727400
EML4 - ALK ALK C1156Y Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) inhibited proliferation of transformed cells expressing EML4-ALK with ALK C1156Y in culture (PMID: 25727400). 25727400
EML4 - ALK ALK S1206Y Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK S1206Y demonstrated resistance to Xalkori (crizotinib) in culture (PMID: 25727400). 25727400