Reference Detail

Ref Type Journal Article
PMID (25421750)
Authors Ceccon M, Mologni L, Giudici G, Piazza R, Pirola A, Fontana D, Gambacorti-Passerini C
Title Treatment Efficacy and Resistance Mechanisms Using the Second-Generation ALK Inhibitor AP26113 in Human NPM-ALK-Positive Anaplastic Large Cell Lymphoma.
Journal Molecular cancer research : MCR
Vol 13
Issue 4
Date 2015 Apr
URL
Abstract Text ALK is a tyrosine kinase receptor involved in a broad range of solid and hematologic tumors. Among 70% to 80% of ALK(+) anaplastic large cell lymphomas (ALCL) are caused by the aberrant oncogenic fusion protein NPM-ALK. Crizotinib was the first clinically relevant ALK inhibitor, now approved for the treatment of late-stage and metastatic cases of lung cancer. However, patients frequently develop drug resistance to Crizotinib, mainly due to the appearance of point mutations located in the ALK kinase domain. Fortunately, other inhibitors are available and in clinical trial, suggesting the potential for second-line therapies to overcome Crizotinib resistance. This study focuses on the ongoing phase I/II trial small-molecule tyrosine kinase inhibitor (TKI) AP26113, by Ariad Pharmaceuticals, which targets both ALK and EGFR. Two NPM-ALK(+) human cell lines, KARPAS-299 and SUP-M2, were grown in the presence of increasing concentrations of AP26113, and eight lines were selected that demonstrated resistance. All lines show IC50 values higher (130 to 1,000-fold) than the parental line. Mechanistically, KARPAS-299 populations resistant to AP26113 show NPM-ALK overexpression, whereas SUP-M2-resistant cells harbor several point mutations spanning the entire ALK kinase domain. In particular, amino acid substitutions: L1196M, S1206C, the double F1174V+L1198F and L1122V+L1196M mutations were identified. The knowledge of the possible appearance of new clinically relevant mechanisms of drug resistance is a useful tool for the management of new TKI-resistant cases.This work defines reliable ALCL model systems of AP26113 resistance and provides a valuable tool in the management of all cases of relapse upon NPM-ALK-targeted therapy.

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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
Variant Impact Protein Effect Variant Description Associated with drug Resistance
D1203N missense unknown ALK D1203N lies within the protein kinase domain of the Alk protein (UniProt.org). D1203N has been demonstrated to occur as a secondary drug resistance mutation in the context of NPM1-ALK and ALK L1196M (PMID: 25421750, PMID: 27432227, PMID: 28434515), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Mar 2019). Y
L1122V missense unknown ALK L1122V lies within the protein kinase domain of the Alk protein (UniProt.org). L1122V has been demonstrated to occur as a secondary drug resistance mutation in the context of NPM1-ALK (PMID: 25421750), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Mar 2019). Y
L1196M missense gain of function - predicted ALK L1196M lies within the protein kinase domain of the Alk protein (UniProt.org). L1196M is predicted to confer a gain of function to the Alk protein as demonstrated by transformation activity and modest autophosphorylation of Alk in culture (PMID: 25517749), and confers resistance to Alk inhibitors in the context of ALK rearrangements in culture (PMID: 21613408, PMID: 25421750). Y
P1139S missense unknown ALK P1139S lies within the protein kinase domain of the Alk protein (UniProt.org). P1139S has been demonstrated to occur as a secondary drug resistance mutation in the context of NPM1-ALK (PMID: 25421750), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Mar 2019). Y
S1206C missense unknown ALK S1206C lies within the protein kinase domain of the Alk protein (UniProt.org). S1206C has been demonstrated to occur as a secondary drug resistance mutation in the context of NPM1-ALK (PMID: 25421750), 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 amp anaplastic large cell lymphoma resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, anaplastic large cell lymphoma cell lines harboring an amplification of NPM1-ALK were resistant to Zykadia (ceritinib) treatment in culture (PMID: 25421750). 25421750
NPM1-ALK ALK F1174V ALK L1198F Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK F1174V and ALK L1198F were resistant to Zykadia (ceritinib) treatment in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1198F Advanced Solid Tumor sensitive Crizotinib Preclinical - Cell culture Actionable In a preclinical trial, Xalkori (crizotinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK L1198F in culture (PMID: 25421750). 25421750
NPM1-ALK Advanced Solid Tumor sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) inhibited growth of transformed cells expressing NPM1-ALK in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1196M 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 L1196M in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1122V Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK L1122V were resistant to ASP3026 treatment in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1198F Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK L1198F were resistant to Alecensa (alectinib) treatment in culture (PMID: 25421750). 25421750
NPM1-ALK ALK F1174V ALK L1198F Advanced Solid Tumor sensitive Crizotinib Preclinical - Cell culture Actionable In a preclinical trial, Xalkori (crizotinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK F1174V and ALK L1198F in culture (PMID: 25421750). 25421750
NPM1-ALK ALK P1139S Advanced Solid Tumor sensitive Crizotinib Preclinical - Cell culture Actionable In a preclinical trial, Xalkori (crizotinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK P1139S in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1122V Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK L1122V were resistant to Zykadia (ceritinib) treatment in culture (PMID: 25421750). 25421750
NPM1-ALK ALK F1174V ALK L1198F Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK F1174V and ALK L1198F were resistant to ASP3026 treatment in culture (PMID: 25421750). 25421750
NPM1-ALK amp anaplastic large cell lymphoma resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, anaplastic large cell lymphoma cell lines harboring an amplification of NPM1-ALK were resistant to Xalkori (crizotinib) treatment in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1196M Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK L1196M were resistant to ASP3026 treatment in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1122V ALK L1196M Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK L1122V and ALK L1196M were resistant to ASP3026 treatment in culture (PMID: 25421750). 25421750
NPM1-ALK anaplastic large cell lymphoma sensitive Alectinib Preclinical - Cell culture Actionable In a preclinical study, Alecensa (alectinib) inhibited growth of an anaplastic large cell lymphoma cell line harboring NPM1-ALK in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1122V Advanced Solid Tumor resistant Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK L1122V were resistant to Alunbrig (brigatinib) treatment in culture (PMID: 25421750). 25421750
NPM1-ALK Advanced Solid Tumor sensitive ASP3026 Preclinical - Cell culture Actionable In a preclinical study, ASP3026 inhibited growth of transformed cells expressing NPM1-ALK in culture (PMID: 25421750). 25421750
NPM1-ALK anaplastic large cell lymphoma sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) inhibited growth of an anaplastic large cell lymphoma cell line harboring NPM1-ALK in culture (PMID: 25421750). 25421750
NPM1-ALK ALK S1206C Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK and ALK S1206C were resistant to ASP3026 treatment in culture (PMID: 25421750). 25421750
NPM1-ALK ALK F1174V 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 F1174V in culture (PMID: 25421750). 25421750
NPM1-ALK ALK P1139S Advanced Solid Tumor sensitive Alectinib Preclinical - Cell culture Actionable In a preclinical trial, Alecensa (alectinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK P1139S in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1196M ALK D1203N Advanced Solid Tumor decreased response Alectinib Preclinical - Cell culture Actionable In a preclinical trial, Alecensa (alectinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK L1196M and ALK D1203N to a lesser degree than cells expressing NPM1-ALK in culture (PMID: 25421750). 25421750
NPM1-ALK ALK S1206C Advanced Solid Tumor decreased response Ceritinib Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK S1206C to a lesser degree than cells expressing NPM1-ALK in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1122V ALK L1196M Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK L1122V and ALK L1196M were resistant to Xalkori (crizotinib) treatment in culture (PMID: 25421750). 25421750
NPM1-ALK ALK F1174V ALK L1198F Advanced Solid Tumor resistant Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK F1174V and ALK1198F were resistant to Alunbrig (brigatinib) treatment in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1122V Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK L1122V were resistant to Alecensa (alectinib) treatment in culture (PMID: 25421750). 25421750
NPM1-ALK ALK P1139S Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) inhibited growth of transformed cells expressing ALK P1139S in the context of NPM1-ALK in culture (PMID: 25421750). 25421750
NPM1-ALK ALK S1206C Advanced Solid Tumor resistant Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK S1206C were resistant to Alunbrig (brigatinib) treatment in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1122V ALK L1196M anaplastic large cell lymphoma resistant Brigatinib Preclinical - Cell culture Actionable In a preclinical study, anaplastic large cell lymphoma cell lines harboring NPM1-ALK with ALK L1122V and ALK L1196M were resistant to Alunbrig (brigatinib) in culture (PMID: 25421750). 25421750
NPM1-ALK Advanced Solid Tumor sensitive Alectinib Preclinical - Cell culture Actionable In a preclinical study, Alecensa (alectinib) inhibited growth of transformed cells expressing NPM1-ALK in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1122V ALK L1196M Advanced Solid Tumor resistant Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK L1122V and ALK L1196M were resistant to Alunbrig (brigatinib) treatment in culture (PMID: 25421750). 25421750
NPM1-ALK ALK F1174V Advanced Solid Tumor decreased response Alectinib Preclinical - Cell culture Actionable In a preclinical study, Alecensa (alectinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK F1174V to a lesser degree than cells expressing NPM1-ALK in culture (PMID: 25421750). 25421750
NPM1-ALK anaplastic large cell lymphoma sensitive ASP3026 Preclinical - Cell culture Actionable In a preclinical study, ASP3026 inhibited growth of an anaplastic large cell lymphoma cell line harboring NPM1-ALK in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1196M Advanced Solid Tumor sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical trial, Zykadia (ceritinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK L1196M in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1196M ALK D1203N Advanced Solid Tumor decreased response Ceritinib Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK L1196M and ALK D1203N to a lesser degree than cells expressing NPM1-ALK in culture (PMID: 25421750). 25421750
NPM1-ALK ALK P1139S Advanced Solid Tumor sensitive ASP3026 Preclinical - Cell culture Actionable In a preclinical study, ASP3026 inhibited growth of transformed cells expressing NPM1-ALK with ALK P1139S in culture (PMID: 25421750). 25421750
NPM1-ALK amp anaplastic large cell lymphoma resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, anaplastic large cell lymphoma cell lines harboring an amplification of NPM1-ALK were resistant to ASP3026 treatment in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1196M Advanced Solid Tumor decreased response Alectinib Preclinical - Cell culture Actionable In a preclinical trial, Alecensa (alectinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK L1196M to a lesser degree than cells expressing NPM1-ALK in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1196M Advanced Solid Tumor decreased response Crizotinib Preclinical - Cell culture Actionable In a preclinical trial, Xalkori (crizotinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK L1196M to a lesser degree than cells expressing NPM1-ALK in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1198F Advanced Solid Tumor resistant Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK L1198F were resistant to Alunbrig (brigatinib) treatment in culture (PMID: 25421750). 25421750
NPM1-ALK ALK F1174V Advanced Solid Tumor sensitive Crizotinib Preclinical - Cell culture Actionable In a preclinical trial, Xalkori (crizotinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK F1174V in culture (PMID: 25421750). 25421750
NPM1-ALK ALK F1174V ALK L1198F Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK F1174V and ALK L1198F were resistant to Alecensa (alectinib) treatment in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1196M ALK D1203N Advanced Solid Tumor sensitive ASP3026 Preclinical - Cell culture Actionable In a preclinical study, ASP3026 inhibited growth of transformed cells expressing NPM1-ALK with ALK L1196M and ALK D1203N in culture (PMID: 25421750). 25421750
NPM1-ALK amp anaplastic large cell lymphoma decreased response Alectinib Preclinical - Cell culture Actionable In a preclinical study, anaplastic large cell lymphoma cell lines harboring an amplification of NPM1-ALK demonstrated a decreased response compared to parental cell lines harboring NPM1-ALK when treated with Alecensa (alectinib) in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1198F Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK L1198F were resistant to Zykadia (ceritinib) treatment in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1196M ALK D1203N Advanced Solid Tumor resistant Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK L1196M and ALK D1203N were resistant to Alunbrig (brigatinib) treatment in culture (PMID: 25421750). 25421750
NPM1-ALK ALK S1206C Advanced Solid Tumor decreased response Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) inhibited growth of transformed cells expressing NPM1-ALK ALK S1206C to a lesser degree than cells expressing NPM1-ALK in culture (PMID: 25421750). 25421750
NPM1-ALK ALK F1174V Advanced Solid Tumor predicted - sensitive ASP3026 Preclinical - Cell culture Actionable In a preclinical trial, ASP3026 inhibited growth of transformed cells expressing NPM1-ALK with ALK F1174V, but to a lesser degree than cells expressing NPM1-ALK in culture (PMID: 25421750). 25421750
NPM1-ALK ALK F1174V Advanced Solid Tumor sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical trial, Zykadia (ceritinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK F1174V in culture (PMID: 25421750). 25421750
NPM1-ALK ALK S1206C Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK S1206C were resistant to Alecensa (alectinib) treatment in culture (PMID: 25421750). 25421750
NPM1-ALK ALK F1174V ALK L1198F anaplastic large cell lymphoma resistant Brigatinib Preclinical - Cell culture Actionable In a preclinical study, anaplastic large cell lymphoma cell lines harboring NPM1-ALK with ALK F1174V and ALK L1198F were resistant to Alunbrig (brigatinib) in culture (PMID: 25421750). 25421750
NPM1-ALK Advanced Solid Tumor sensitive Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) inhibited growth of transformed cells expressing NPM1-ALK in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1198F Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK L1198F were resistant to ASP3026 treatment in culture (PMID: 25421750). 25421750
NPM1-ALK ALK S1206C anaplastic large cell lymphoma resistant Brigatinib Preclinical - Cell culture Actionable In a preclinical study, anaplastic large cell lymphoma cell lines harboring NPM1-ALK ALK S1206C were resistant to Alunbrig (brigatinib) in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1196M ALK D1203N Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK L1196M and ALK D1203N were resistant to Xalkori (crizotinib) treatment in culture (PMID: 25421750). 25421750
NPM1-ALK Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) inhibited growth of transformed cells expressing NPM1-ALK in culture (PMID: 25421750). 25421750
NPM1-ALK ALK L1122V ALK L1196M Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK L1122V and ALK L1196M were resistant to Alecensa (alectinib) treatment in culture (PMID: 25421750). 25421750
NPM1-ALK ALK P1139S Advanced Solid Tumor decreased response Ceritinib Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK P1139S to a lesser degree than cells expressing NPM1-ALK in culture (PMID: 25421750). 25421750
NPM1-ALK amp anaplastic large cell lymphoma resistant Brigatinib Preclinical - Cell culture Actionable In a preclinical study, anaplastic large cell lymphoma cell lines harboring an amplification of NPM1-ALK were resistant to Alunbrig (brigatinib) in culture (PMID: 25421750). 25421750