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	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	17	23	2011 Dec 01	7394-401	Clin Cancer Res

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	ALK1\|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: 25749034, PMID: 21948233).	Oncogene

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	G1123D	missense	unknown	ALK G1123D lies within the protein kinase domain of the Alk protein (UniProt.org). G1123D has been demonstrated to confer drug resistance in cell culture (PMID: 21948233), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Aug 2024).	Y
ALK	G1123S	missense	unknown	ALK G1123S lies within the protein kinase domain of the Alk protein (UniProt.org). G1123S has been demonstrated to confer drug resistance in culture (PMID: 26134233, PMID: 21948233), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Aug 2024).	Y
ALK	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 Alk phosphorylation (PMID: 21948233) and has been demonstrated to confer resistance to Alk inhibitors in the context of EML4-ALK (PMID: 21948233, PMID: 22034911).	Y
ALK	L1198P	missense	gain of function - predicted	ALK L1198P lies within the protein kinase domain of the Alk protein (UniProt.org). L1198P results in increased phosphorylation of Alk and has been demonstrated to confer resistance to Alk inhibitors in the context of EML4-ALK in culture (PMID: 21948233), and therefore, is predicted to lead to a gain of Alk protein function.	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ALK G1123D ALK F1174L	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
EML4 - ALK ALK G1269S	Advanced Solid Tumor	resistant	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1269S in the context of EML4-ALK were resistant to Xalkori (crizotinib) in culture (PMID: 21948233).	21948233
ALK G1123S ALK F1174L	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
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 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 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
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	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