Reference Detail

Ref Type Journal Article
PMID (25749034)
Authors Mologni L, Ceccon M, Pirola A, Chiriano G, Piazza R, Scapozza L, Gambacorti-Passerini C
Title NPM/ALK mutants resistant to ASP3026 display variable sensitivity to alternative ALK inhibitors but succumb to the novel compound PF-06463922.
Journal Oncotarget
Vol 6
Issue 8
Date 2015 Mar 20
URL
Abstract Text ALK is involved in the onset of several tumors. Crizotinib (XalkoriTM), a potent ALK inhibitor, represents the current front-line treatment for ALK+ NSCLC and shows great clinical efficacy. However, resistant disease often develops after initial response. ASP3026 is a novel second-generation ALK inhibitor with activity on crizotinib-resistant ALK-L1196M gatekeeper mutant. As resistance is likely to be a relevant hurdle for any drug, we sought to determine the resistance profile of ASP3026 in the context of NPM/ALK+ ALCL. We selected six ASP3026-resistant cell lines by culturing human ALCL cells in the presence of increasing concentrations of drug. The established resistant cell lines carry several point mutations in the ALK kinase domain (G1128S, C1156F, I1171N/T, F1174I, N1178H, E1210K and C1156F/D1203N were the most frequent) that are shown to confer resistance to ASP3026 in the Ba/F3 cell model. All mutants were profiled for cross-resistance against a panel of clinically relevant inhibitors including ceritinib, alectinib, crizotinib, AP26113 and PF-06463922. Finally, a genetically heterogeneous ASP3026-resistant cell line was exposed to second-line treatment simulations with all inhibitors. The population evolved according to relative sensitivity of its mutant subclones to the various drugs. Compound PF-06463922 did not allow the outgrowth of any resistant clone, at non-toxic doses.

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Gene Name Source Synonyms Protein Domains Gene Description Gene Role
ALK NCBI CD246|NBLST3 ALK, anaplastic lymphoma kinase, is a receptor in the insulin receptor superfamily and is a key regulator of neuronal development (PMID: 21502284) and also promotes cell proliferation through activation of MAPK and PI3K signaling pathways (PMID: 27573755). Alk activating mutations, rearrangements, and fusions have been identified in various cancers (PMID: 22649787), including EML4-ALK in non-small cell lung cancer (PMID: 30108712, PMID: 30194140), and a number of mutations confer resistance in the context of Alk fusions (PMID: PMID: 25749034, PMID: 21948233). unknown
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
C1156F missense unknown ALK C1156F lies within the protein kinase domain of the Alk protein (UniProt.org). C1156F has been demonstrated to occur as a secondary drug resistance mutation in the context of NPM1-ALK (PMID: 25749034, PMID: 30322862), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Mar 2019). Y
E1210K missense unknown ALK E1210K lies within the protein kinase domain of the Alk protein (UniProt.org). E1210K has been demonstrated to occur as a secondary drug resistance mutation in the context of NPM1-ALK and EML4-ALK (PMID: 25749034, PMID: 25914136), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Jun 2018). Y
G1128S missense unknown ALK G1128S lies within the protein kinase domain of the Alk protein (UniProt.org). G1128S has been demonstrated to occur as a secondary drug resistance mutation in the context of NPM1-ALK (PMID: 25749034), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Mar 2019). Y
L1196Q missense gain of function - predicted ALK L1196Q lies within the protein kinase domain of the Alk protein (UniProt.org). L1196Q is predicted to confer a gain of function on the Alk protein as indicated by increased phosphorylation of Alk (PMID: 25749034) and has been demonstrated to confer resistance to Alk inhibitors in the context of NPM1-ALK in culture (PMID: 25749034, PMID: 23239810). Y
N1178H missense unknown ALK N1178H lies within the protein kinase domain of the Alk protein (UniProt.org). N1178H has been demonstrated to occur as a secondary drug resistance mutation in the context of NPM1-ALK (PMID: 25749034), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Mar 2019). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NPM1-ALK ALK I1171T Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK I1171T were resistant to Zykadia (ceritinib) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK N1178H anaplastic large cell lymphoma resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, human anaplastic large cell lymphoma cell lines harboring NPM1-ALK with ALK N1178H were resistant to ASP3026 mediated growth inhibition in culture (PMID: 25749034). 25749034
NPM1-ALK ALK C1156F Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK C1156F were resistant to Lorlatinib (PF-06463922) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK F1174I Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorlatinib (PF-06463922) inhibited growth of transformed cells expressing NPM1-ALK with ALK F1174I in culture (PMID: 25749034). 25749034
NPM1-ALK ALK G1128S Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK G1128S in culture (PMID: 25749034). 25749034
NPM1-ALK ALK I1171N Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK I1171N were resistant to Xalkori (critzotinb) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK N1178H Advanced Solid Tumor decreased response ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK N1178H were resistant to ASP3026 in culture (PMID: 25749034). 25749034
NPM1-ALK ALK F1174I Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK F1174I were resistant to ASP3026 relative to wild type NPM1-ALK in culture (PMID: 25749034). 25749034
NPM1-ALK ALK F1174I Advanced Solid Tumor sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK F1174I in culture (PMID: 25749034). 25749034
NPM1-ALK ALK I1171T Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK I1171T were resistant to Alecensa (alectinib) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK E1210K Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK E1210K were resistant to ASP3026 in culture (PMID: 25749034). 25749034
NPM1-ALK ALK N1178H Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK N1178H were resistant to Lorlatinib (PF-06463922) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK I1171N Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK I1171N were resistant to Zykadia (ceritinib) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK I1171N Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK I1171N were resistant to ASP3026 in culture (PMID: 25749034). 25749034
NPM1-ALK ALK G1128S Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK G1128S were resistant to Xalkori (crizotinib) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK F1174I Advanced Solid Tumor sensitive Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK F1174I in culture (PMID: 25749034). 25749034
NPM1-ALK ALK C1156F Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK C1156F were resistant to ASP3026 in culture (PMID: 25749034). 25749034
NPM1-ALK ALK E1210K Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK E1210K were resistant to Alecensa (alectinib) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK C1156F ALK D1203N Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with C1156F and D1203N were resistant to Zykadia (ceritinib) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK N1178H Advanced Solid Tumor resistant Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK N1178H were resistant to Alunbrig (brigatinib) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK C1156F anaplastic large cell lymphoma resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, human anaplastic large cell lymphoma cell lines harboring NPM1-ALK with ALK C1156F were resistant to ASP3026 mediated growth inhibition in culture (PMID: 25749034). 25749034
NPM1-ALK ALK E1210K Advanced Solid Tumor sensitive Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK E1210K in culture (PMID: 25749034). 25749034
NPM1-ALK ALK C1156F Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK C1156F were resistant to Zykadia (ceritinib) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK F1174I anaplastic large cell lymphoma resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, human anaplastic large cell lymphoma cell lines harboring NPM1-ALK with ALK with ALK F1174I were resistant to ASP3026 mediated growth inhibition in culture (PMID: 25749034). 25749034
NPM1-ALK ALK I1171T Advanced Solid Tumor resistant Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK I1171T were resistant to Alunbrig (brigatinib) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK I1171T Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK I1171T were resistant to ASP3026 in culture (PMID: 25749034). 25749034
NPM1-ALK ALK C1156F ALK D1203N Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK C1156F and D1203N were resistant to Xalkori (crizotinib) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK G1128S Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK G1128S were resistant to ASP3026 in culture (PMID: 25749034). 25749034
NPM1-ALK ALK C1156F ALK D1203N Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK C1156F and ALK D1203N were resistant to ASP3026 in culture (PMID: 25749034). 25749034
NPM1-ALK ALK C1156F Advanced Solid Tumor resistant Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK C1156F were resistant to Alunbrig (brigatinib) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK N1178H Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK N1178H were resistant to Zykadia (ceritinib) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK C1156Y anaplastic large cell lymphoma resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, human anaplastic large cell lymphoma cell lines harboring NPM1-ALK with ALK C1156Y were resistant to ASP3026 mediated growth inhibition in culture (PMID: 25749034). 25749034
NPM1-ALK ALK G1128S Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK G1128S were resistant to Zykadia (ceritinib) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK C1156F ALK D1203N Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK C1156F and D1203N were resistant to Alecensa (alectinib) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK E1210K anaplastic large cell lymphoma resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, human anaplastic large cell lymphoma cell lines harboring NPM1-ALK with ALK with ALK E1210K were resistant to ASP3026 mediated growth inhibition in culture (PMID: 25749034). 25749034
NPM1-ALK ALK G1128S Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK G1128S were resistant to Lorlatinib (PF-06463922) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK I1171N Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK I1171N were resistant to Alecensa (alectinib) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK C1156F ALK D1203N Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK C1156F and ALK D1203N were resistant to Lorlatinib (PF-06463922) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK N1178H Advanced Solid Tumor sensitive Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK N1178H in culture (PMID: 25749034). 25749034
NPM1-ALK ALK C1156F Advanced Solid Tumor sensitive Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK C1156F in culture (PMID: 25749034). 25749034
NPM1-ALK ALK C1156F ALK D1203N Advanced Solid Tumor resistant Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK C1156F and D1203N were resistant to Alunbrig (brigatinib) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK N1178H Advanced Solid Tumor sensitive Alectinib Preclinical - Cell culture Actionable In a preclinical study, Alecensa (alectinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK N1178H in culture (PMID: 25749034). 25749034
NPM1-ALK Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorlatinib (PF-06463922) inhibited growth of transformed cells expressing NPM1-ALK in culture (PMID: 25749034). 25749034
NPM1-ALK ALK I1171N anaplastic large cell lymphoma resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, human anaplastic large cell lymphoma cell lines harboring NPM1-ALK with ALK I1171N were resistant to ASP3026 mediated growth inhibition in culture (PMID: 25749034). 25749034
NPM1-ALK ALK L1196Q anaplastic large cell lymphoma resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, human anaplastic large cell lymphoma cell lines harboring NPM1-ALK containing ALK L1196Q were resistant to Xalkori (crizotinib) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK I1171T Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK I1171T were resistant to Xalkori (crizotinib) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK I1171T anaplastic large cell lymphoma resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, human anaplastic large cell lymphoma cell lines harboring NPM1-ALK with ALK I1171T were resistant to ASP3026 mediated growth inhibition in culture (PMID: 25749034). 25749034
NPM1-ALK ALK I1171N Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK I1171N were resistant to Lorlatinib (PF-06463922) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK G1128S anaplastic large cell lymphoma resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, human anaplastic large cell lymphoma cell lines harboring NPM1-ALK with ALK G1128S were resistant to ASP3026 mediated growth inhibition in culture (PMID: 25749034). 25749034
NPM1-ALK ALK E1210K Advanced Solid Tumor resistant Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK E1210K were resistant to Alunbrig (brigatinib) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK E1210K Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with E1210K were resistant to Zykadia (ceritinib) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK I1171N Advanced Solid Tumor resistant Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK I1171N were resistant to Alunbrig (brigatinib) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK E1210K Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK E1210K were resistant to Lorlatinib (PF-06463922) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK L1196Q anaplastic large cell lymphoma sensitive ASP3026 Preclinical - Cell culture Actionable In a preclinical study, ASP3026 inhibited growth of human anaplastic large cell lymphoma cell lines harboring NPM1-ALK containing the crizotinib-resistant mutation ALK L1196Q in culture (PMID: 25749034). 25749034
NPM1-ALK ALK F1174I Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK F1174I in culture (PMID: 25749034). 25749034
NPM1-ALK ALK C1156F Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK C1156F were resistant to Alecensa (alectinib) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK F1174I Advanced Solid Tumor sensitive Alectinib Preclinical - Cell culture Actionable In a preclinical study, Alecensa (alectinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK F1174I in culture (PMID: 25749034). 25749034
NPM1-ALK ALK G1128S Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK G1128S were resistant to Alecensa (alectinib) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK I1171T Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK I1171T were resistant to Lorlatinib (PF-06463922) in culture (PMID: 25749034). 25749034
NPM1-ALK ALK C1156F ALK D1203N anaplastic large cell lymphoma resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, human anaplastic large cell lymphoma cell lines harboring NPM1-ALK with ALK with ALK C1156F and D1203N were resistant to ASP3026 mediated growth inhibition in culture (PMID: 25749034). 25749034