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Ref Type Journal Article
PMID (38448512)
Authors Villa M, Malighetti F, Sala E, Sharma GG, Arosio G, Gemelli M, Manfroni C, Fontana D, Cordani N, Meneveri R, Zambon A, Piazza R, Pagni F, Cortinovis D, Mologni L
Title New pan-ALK inhibitor-resistant EML4::ALK mutations detected by liquid biopsy in lung cancer patients.
Journal Vol Issue Date Pages Journal Short Title
NPJ precision oncology 8 1 2024 Mar 06 29 NPJ Precis Oncol
URL
Abstract Text ALK and ROS1 fusions are effectively targeted by tyrosine kinase inhibitors (TKIs), however patients inevitably relapse after an initial response, often due to kinase domain mutations. We investigated circulating DNA from TKI-relapsed NSCLC patients by deep-sequencing. New EML4::ALK substitutions, L1198R, C1237Y and L1196P, were identified in the plasma of NSCLC ALK patients and characterized in a Ba/F3 cell model. Variants C1237Y and L1196P demonstrated pan-inhibitor resistance across 5 clinical and 2 investigational TKIs.

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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 C1235R missense unknown ALK C1235R lies within the protein kinase domain of the Alk protein (UniProt.org). C1235R has been demonstrated to occur as a secondary drug resistance mutation in the context of ALK compound mutations (PMID: 38448512), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Mar 2024). Y
ALK C1237Y missense gain of function - predicted ALK C1237Y lies within the protein kinase domain of the Alk protein (UniProt.org). C1237Y results in both increased phosphorylation of Alk and proliferation, and has been demonstrated to confer resistance to Alk inhibitors in the context of EML4-ALK in culture (PMID: 38448512), and therefore, is predicted to lead to a gain of Alk protein function. Y
ALK E1154K missense unknown ALK E1154K lies within the protein kinase domain of the Alk protein (UniProt.org). E1154K has been identified in the scientific literature (PMID: 31585938, PMID: 38448512), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Apr 2024).
ALK L1196P missense gain of function - predicted ALK L1196P lies within the protein kinase domain of the Alk protein (UniProt.org). L1196P results in both increased phosphorylation of Alk and proliferation, and has been demonstrated to confer resistance to Alk inhibitors in the context of EML4-ALK in culture (PMID: 38448512), and therefore, is predicted to lead to a gain of Alk protein function. Y
ALK L1198R missense unknown ALK L1198R lies within the protein kinase domain of the Alk protein (UniProt.org). L1198R has been demonstrated to occur as a secondary drug resistance mutation in the context of ALK compound mutations (PMID: 38448512), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Mar 2024). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4 - ALK ALK L1196P Advanced Solid Tumor resistant Brigatinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing EML4-ALK and ALK L1196P were resistant to Alunbrig (brigatinib) in culture (PMID: 38448512). 38448512
EML4 - ALK ALK L1196P Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing EML4-ALK and ALK L1196P were resistant to Alecensa (alectinib) in culture (PMID: 38448512). 38448512
EML4 - ALK ALK L1196P lung non-small cell carcinoma predicted - resistant Lorlatinib Case Reports/Case Series Actionable In a clinical case study, ALK L1196P was identified in the post-progression circulating tumor DNA of a patient with relapsed non-small cell lung cancer harboring EML4-ALK treated with Lorbrena (lorlatinib), and in a preclinical study, cells expressing EML4-ALK and ALK L1196P were resistant to Lorbrena (lorlatinib) in culture (PMID: 38448512). 38448512
EML4 - ALK ALK C1237Y Advanced Solid Tumor resistant Repotrectinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing EML4-ALK and ALK C1237Y were resistant to Augtyro (repotrectinib) in culture (PMID: 38448512). 38448512
EML4 - ALK ALK L1196M ALK G1202R Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing EML4-ALK, ALK L1196M, and ALK G1202R were resistant to Alecensa (alectinib) in culture (PMID: 38448512). 38448512
EML4 - ALK ALK L1196P Advanced Solid Tumor resistant Repotrectinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing EML4-ALK and ALK L1196P were resistant to Augtyro (repotrectinib) in culture (PMID: 38448512). 38448512
EML4 - ALK ALK L1198R Advanced Solid Tumor predicted - resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing EML4-ALK and ALK L1198R were moderately resistant to Zykadia (ceritinib) in culture (PMID: 38448512). 38448512
EML4 - ALK ALK L1198R Advanced Solid Tumor predicted - resistant Brigatinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing EML4-ALK and ALK L1198R were moderately resistant to Alunbrig (brigatinib) in culture (PMID: 38448512). 38448512
EML4 - ALK ALK L1196P Advanced Solid Tumor resistant TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, cells expressing EML4-ALK and ALK L1196P were resistant to TPX-0131 in culture (PMID: 38448512). 38448512
EML4 - ALK ALK C1237Y Advanced Solid Tumor resistant Brigatinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing EML4-ALK and ALK C1237Y were resistant to Alunbrig (brigatinib) in culture (PMID: 38448512). 38448512
EML4 - ALK ALK C1237Y Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing EML4-ALK and ALK C1237Y were resistant to Alecensa (alectinib) in culture (PMID: 38448512). 38448512
EML4 - ALK ALK L1196P Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing EML4-ALK and ALK L1196P were resistant to Xalkori (crizotinib) in culture (PMID: 38448512). 38448512
EML4 - ALK ALK L1196M ALK G1202R Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing EML4-ALK, ALK L1196M, and ALK G1202R were resistant to Xalkori (crizotinib) in culture (PMID: 38448512). 38448512
EML4 - ALK ALK C1237Y Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing EML4-ALK and ALK C1237Y were resistant to Zykadia (ceritinib) in culture (PMID: 38448512). 38448512
EML4 - ALK ALK C1235R ALK C1237Y lung non-small cell carcinoma predicted - resistant Brigatinib Case Reports/Case Series Actionable In a clinical case study, a patient with relapsed non-small cell lung cancer harboring EML4-ALK developed progressive disease while on treatment with Alunbrig (brigatinib), and was found to have acquired ALK C1235R and ALK C1237Y in trans by liquid biopsy (PMID: 38448512). 38448512
EML4 - ALK ALK L1198R lung non-small cell carcinoma predicted - resistant Crizotinib Preclinical - Cell culture Actionable In a clinical case study, ALK L1198R was identified in the post-progression circulating tumor DNA of a patient with relapsed non-small cell lung cancer harboring EML4-ALK treated with Xalkori (crizotinib), and in a preclinical study, cells expressing EML4-ALK and ALK L1196P were resistant to Xalkori (crizotinib) in culture (PMID: 38448512). 38448512
EML4 - ALK ALK L1196M ALK G1202R Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing EML4-ALK, ALK L1196M, and ALK G1202R were resistant to Zykadia (ceritinib) in culture (PMID: 38448512). 38448512
EML4 - ALK ALK L1196M ALK G1202R lung non-small cell carcinoma resistant Brigatinib Case Reports/Case Series Actionable In a clinical case study, ALK L1196M and ALK G1202R were identified in the post-progression circulating tumor DNA of a patient with non-small cell lung cancer harboring EML4-ALK who progressed on treatment with Alunbrig (brigatinib), and in a preclinical study, cells expressing EML4-ALK, ALK L1196M, and ALK G1202R were resistant to Alunbrig (brigatinib) in culture (PMID: 38448512, PMID: 36806896). 36806896 38448512
EML4 - ALK ALK L1196P Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing EML4-ALK and ALK L1196P were resistant to Zykadia (ceritinib) in culture (PMID: 38448512). 38448512
EML4 - ALK ALK C1237Y Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing EML4-ALK and ALK C1237Y were resistant to Lorbrena (lorlatinib) in culture (PMID: 38448512). 38448512
EML4 - ALK ALK C1237Y Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing EML4-ALK and ALK C1237Y were resistant to Xalkori (crizotinib) in culture (PMID: 38448512). 38448512
EML4 - ALK ALK L1198R Advanced Solid Tumor predicted - resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing EML4-ALK and ALK L1198R were moderately resistant to Lorbrena (lorlatinib) in culture (PMID: 38448512). 38448512
EML4 - ALK ALK L1196M ALK G1202R Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing EML4-ALK, ALK L1196M, and ALK G1202R were resistant to Lorbrena (lorlatinib) in culture (PMID: 38448512). 38448512
EML4 - ALK ALK C1237Y Advanced Solid Tumor resistant TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, cells expressing EML4-ALK and ALK C1237Y were resistant to TPX-0131 in culture (PMID: 38448512). 38448512
EML4 - ALK ALK L1198R Advanced Solid Tumor predicted - resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing EML4-ALK and ALK L1198R were moderately resistant to Alecensa (alectinib) in culture (PMID: 38448512). 38448512