Heuckmann, Johannes M., Hoelzel, Michael, Sos, Martin L., Heynck, Stefanie, Balke-Want, Hyatt, Koker, Mirjam, Peifer, Martin ORCID: 0000-0002-5243-5503, Weiss, Jonathan, Lovly, Christine M., Gruetter, Christian, Rauh, Daniel ORCID: 0000-0002-1970-7642, Pao, William and Thomas, Roman K. (2011). ALK Mutations Conferring Differential Resistance to Structurally Diverse ALK Inhibitors. Clin. Cancer Res., 17 (23). S. 7394 - 7402. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1078-0432

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Abstract

Purpose: 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. Experimental Design: By applying orthogonal functional mutagenesis screening approaches, we screened for mutations inducing resistance to the aminopyridine PF02341066 (crizotinib) and/or the diaminopyrimidine TAE684. Results: 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. Conclusions: 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. Clin Cancer Res; 17(23); 7394-401. (C)2011 AACR.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Heuckmann, Johannes M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoelzel, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sos, Martin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heynck, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Balke-Want, HyattUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koker, MirjamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, MartinUNSPECIFIEDorcid.org/0000-0002-5243-5503UNSPECIFIED
Weiss, JonathanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lovly, Christine M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gruetter, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rauh, DanielUNSPECIFIEDorcid.org/0000-0002-1970-7642UNSPECIFIED
Pao, WilliamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-484721
DOI: 10.1158/1078-0432.CCR-11-1648
Journal or Publication Title: Clin. Cancer Res.
Volume: 17
Number: 23
Page Range: S. 7394 - 7402
Date: 2011
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 1078-0432
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ANAPLASTIC LYMPHOMA KINASE; CELL LUNG-CANCER; EML4-ALK FUSION GENE; ACTIVATING MUTATIONS; EGFR INHIBITORS; NEUROBLASTOMA; RECEPTOR; IDENTIFICATION; ADENOCARCINOMA; MUTAGENESISMultiple languages
OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/48472

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