Lovly, Christine M., McDonald, Nerina T., Chen, Heidi, Ortiz-Cuaran, Sandra, Heukamp, Lukas C., Yan, Yingjun ORCID: 0000-0001-6963-7112, Florin, Alexandra, Ozretic, Luka, Lim, Diana, Wang, Lu ORCID: 0000-0002-0073-0666, Chen, Zhao, Chen, Xi, Lu, Pengcheng, Paik, Paul K., Shen, Ronglai, Jin, Hailing, Buettner, Reinhard, Ansen, Sascha, Perner, Sven, Brockmann, Michael, Bos, Marc, Wolf, Juergen, Gardizi, Masyar, Wright, Gavin M., Solomon, Benjamin, Russell, Prudence A., Rogers, Toni-Maree, Suehara, Yoshiyuki, Red-Brewer, Monica, Tieu, Rudy, de Stanchina, Elisa, Wang, Qingguo ORCID: 0000-0002-5125-3724, Zhao, Zhongming, Johnson, David H., Horn, Leora, Wong, Kwok-Kin, Thomas, Roman K., Ladanyi, Marc and Pao, William (2014). Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer. Nat. Med., 20 (9). S. 1027 - 1035. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1546-170X

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Abstract

Crizotinib, a selective tyrosine kinase inhibitor (TKI), shows marked activity in patients whose lung cancers harbor fusions in the gene encoding anaplastic lymphoma receptor tyrosine kinase (ALK), but its efficacy is limited by variable primary responses and acquired resistance. In work arising from the clinical observation of a patient with ALKfusion-positive lung cancer who had an exceptional response to an insulin-like growth factor 1 receptor (IGF-1R)-specific antibody, we define a therapeutic synergism between ALK and IGF-1R inhibitors. Similar to IGF-1R, ALK fusion proteins bind to the adaptor insulin receptor substrate 1 (IRS-1), and IRS-1 knockdown enhances the antitumor effects of ALK inhibitors. In models of ALK TKI resistance, the IGF-1R pathway is activated, and combined ALK and IGF-1R inhibition improves therapeutic efficacy. Consistent with this finding, the levels of IGF-1R and IRS-1 are increased in biopsy samples from patients progressing on crizotinib monotherapy. Collectively these data support a role for the IGF-1R-IRS-1 pathway in both ALK TKI-sensitive and ALK TKI-resistant states and provide a biological rationale for further clinical development of dual ALK and IGF-1R inhibitors.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Lovly, Christine M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McDonald, Nerina T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, HeidiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ortiz-Cuaran, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heukamp, Lukas C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yan, YingjunUNSPECIFIEDorcid.org/0000-0001-6963-7112UNSPECIFIED
Florin, AlexandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ozretic, LukaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lim, DianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, LuUNSPECIFIEDorcid.org/0000-0002-0073-0666UNSPECIFIED
Chen, ZhaoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, XiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lu, PengchengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Paik, Paul K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shen, RonglaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jin, HailingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ansen, SaschaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perner, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brockmann, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bos, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gardizi, MasyarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wright, Gavin M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Solomon, BenjaminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Russell, Prudence A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rogers, Toni-MareeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Suehara, YoshiyukiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Red-Brewer, MonicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tieu, RudyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Stanchina, ElisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, QingguoUNSPECIFIEDorcid.org/0000-0002-5125-3724UNSPECIFIED
Zhao, ZhongmingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Johnson, David H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Horn, LeoraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wong, Kwok-KinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ladanyi, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pao, WilliamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-431351
DOI: 10.1038/nm.3667
Journal or Publication Title: Nat. Med.
Volume: 20
Number: 9
Page Range: S. 1027 - 1035
Date: 2014
Publisher: NATURE PUBLISHING GROUP
Place of Publication: NEW YORK
ISSN: 1546-170X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TYROSINE KINASE INHIBITORS; ACQUIRED-RESISTANCE; RECEPTOR; IDENTIFICATION; CRIZOTINIB; MECHANISM; POTENT; CELLSMultiple languages
Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/43135

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