Reference Detail

Ref Type Journal Article
PMID (21948233)
Authors Heuckmann JM, Hölzel M, Sos ML, Heynck S, Balke-Want H, Koker M, Peifer M, Weiss J, Lovly CM, Grütter C, Rauh D, Pao W, Thomas RK
Title ALK mutations conferring differential resistance to structurally diverse ALK inhibitors.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 17
Issue 23
Date 2011 Dec 01
URL
Abstract Text EML4-ALK fusions define a subset of lung cancers that can be effectively treated with anaplastic lymphoma kinase (ALK) inhibitors. Unfortunately, the duration of response is heterogeneous and acquired resistance limits their ultimate efficacy. Thus, a better understanding of resistance mechanisms will help to enhance tumor control in EML4-ALK-positive tumors.By applying orthogonal functional mutagenesis screening approaches, we screened for mutations inducing resistance to the aminopyridine PF02341066 (crizotinib) and/or the diaminopyrimidine TAE684.Here, we show that the resistance mutation, L1196M, as well as other crizotinib resistance mutations (F1174L and G1269S), are highly sensitive to the structurally unrelated ALK inhibitor TAE684. In addition, we identified two novel EML4-ALK resistance mutations (L1198P and D1203N), which unlike previously reported mutations, induced resistance to both ALK inhibitors. An independent resistance screen in ALK-mutant neuroblastoma cells yielded the same L1198P resistance mutation but defined two additional mutations conferring resistance to TAE684 but not to PF02341066.Our results show that different ALK resistance mutations as well as different ALK inhibitors impact the therapeutic efficacy in the setting of EML4-ALK fusions and ALK mutations.

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Molecular Profile Treatment Approach
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 Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
G1123D missense unknown ALK G1123D lies within the protein kinase domain of the Alk protein (UniProt.org). G1123D has been demonstrated to occur as a secondary drug resistance mutation in culture (PMID: 21948233), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Mar 2019). Y
G1123S missense unknown ALK G1123S lies within the protein kinase domain of the Alk protein (UniProt.org). G1123S has been demonstrated to occur as a secondary drug resistance mutation in the context of ALK rearrangement (PMID: 26134233, PMID: 21948233), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Mar 2019). Y
G1269S missense gain of function - predicted ALK G1269S lies within the protein kinase domain of the Alk protein (UniProt.org). G1269S is predicted to confer a gain of function on the Alk protein as indicated by increased phosphorylation of Alk (PMID: 21948233) and has been demonstrated to confer resistance to Alk inhibitors in the context of EML4-ALK (PMID: 21948233, PMID: 22034911). Y
L1198P missense gain of function - predicted ALK L1198P lies within the protein kinase domain of the Alk protein (UniProt.org). L1198P is predicted to confer a gain of function on the Alk protein as indicated by increased phosphorylation of Alk and has been demonstrated to confer resistance to Alk inhibitors in the context of EML4-ALK in culture (PMID: 21948233). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK F1174L ALK L1198P neuroblastoma resistant TAE684 Preclinical - Cell culture Actionable In a preclinical study, expression of ALK L1198P in neuroblastoma cells harboring an ALK F1174L mutation resulted in resistance to TAE684 in culture (PMID: 21948233). 21948233
EML4-ALK ALK L1198P Advanced Solid Tumor resistant TAE684 Preclinical - Cell culture Actionable In a preclinical study, transformed cells overexpressing ALK L1198P in the context of EML4-ALK were resistant to TAE684 in culture (PMID: 21948233). 21948233
EML4-ALK ALK L1198P Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells overexpressing ALK L1198P in the context of EML4-ALK were resistant to Xalkori (crizotinib) in culture (PMID: 21948233). 21948233
ALK F1174L ALK L1198P neuroblastoma resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, expression of ALK L1198P in neuroblastoma cells harboring an ALK F1174L mutation resulted in resistance to Xalkori (crizotinib) in culture (PMID: 21948233). 21948233
EML4-ALK ALK D1203N Advanced Solid Tumor resistant TAE684 Preclinical - Cell culture Actionable In a preclinical study, transformed cells overexpressing ALK D1203N in the context of EML4-ALK were resistant to TAE684 in culture (PMID: 21948233). 21948233
ALK F1174L ALK G1123D neuroblastoma resistant TAE684 Preclinical - Cell culture Actionable In a preclinical study, expression of ALK G1123D in neuroblastoma cells harboring an ALK F1174L mutation resulted in resistance to TAE684 in culture (PMID: 21948233). 21948233
ALK F1174L ALK G1123S neuroblastoma resistant TAE684 Preclinical - Cell culture Actionable In a preclinical study, expression of ALK G1123S in neuroblastoma cells harboring an ALK F1174L mutation resulted in resistance to TAE684 in culture (PMID: 21948233). 21948233