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Nat Med. 2014 Sep;20(9):1027-34. doi: 10.1038/nm.3667. Epub 2014 Aug 31.

Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer.

Author information

1
Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
2
Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, USA.
3
Department of Translational Genomics, Center of Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany.
4
1] Department of Pathology, Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany. [2] New Oncology, Cologne, Germany.
5
Department of Pathology, Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany.
6
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
7
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
8
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
9
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
10
Department of Internal Medicine (Department I), Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany.
11
Department of Prostate Cancer Research, Institute of Pathology, Center of Integrated Oncology Köln-Bonn, University Hospital of Bonn, Bonn, Germany.
12
Department of Pathology, Hospital Merheim, Cologne, Germany.
13
1] Department of Translational Genomics, Center of Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany. [2] Department of Internal Medicine (Department I), Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany.
14
Department of Surgery, University of Melbourne, St. Vincent's Hospital, Melbourne, Victoria, Australia.
15
Division of Hematology and Medical Oncology, Peter MacCallum Cancer Center, Melbourne, Australia.
16
Department of Anatomical Pathology, St. Vincent's Hospital, Melbourne, Victoria, Australia.
17
Department of Pathology, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
18
Anti-tumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
19
Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, USA.
20
Department of Medicine, UT Southwestern School of Medicine, Dallas, Texas, USA.
21
1] Department of Translational Genomics, Center of Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany. [2] Department of Pathology, Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany.

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 ALK fusion-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.

PMID:
25173427
PMCID:
PMC4159407
DOI:
10.1038/nm.3667
[Indexed for MEDLINE]
Free PMC Article

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