Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer
Open accessAbstract
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.
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Self-citation
- Authors
- Lovly, C. M., McDonald, N. T., Chen, H., Ortiz-Cuaran, S., Heukamp, L. C., Yan, Y., Florin, A., Ozretić, L., Lim, D., Wang, L., Chen, Z., Chen, X., Lu, P., Paik, P. K., Shen, R., Jin, H., Buettner, R., Ansén, S., Perner, S., Brockmann, M., Bos, M., Wolf, J., Gardizi, M., Wright, G. M., Solomon, B., Russell, P. A., Rogers, T.-M., Suehara, Y., Red-Brewer, M., Tieu, R., de Stanchina, E., Wang, Q., Zhao, Z., Johnson, D. H., Horn, L., Wong, K.-K., Thomas, R. K., Ladanyi, M., & Pao, W.
- Affiliations
- Vanderbilt University (US)
- University Hospital Cologne (DE)
- Memorial Sloan Kettering Cancer Center (US)
- University Hospital Bonn (DE)
- The University of Melbourne (AU)
- Peter MacCallum Cancer Centre (AU)
- St Vincent's Hospital Melbourne (AU)
- The University of Texas Southwestern Medical Center (US)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Lovly, Christine M
- ORCID
- Lovly, Christine M
- Chen, Heidi
- Heukamp, Lukas C
- Yan, Yingjun
- Florin, Alexandra
- Lim, Diana
- Chen, Xi
- Paik, Paul K
- Shen, Ronglai
- Jin, Hailing
- Perner, Sven
- Wolf, Jürgen
- Wright, Gavin M
- Solomon, Benjamin
- Russell, Prudence A
- Suehara, Yoshiyuki
- Wang, Qingguo
- Zhao, Zhongming
- Johnson, David H
- Horn, Leora
- Wong, Kwok-Kin
- Thomas, Roman K
- Ladanyi, Marc
- Pao, William
- Venue
- Nature Medicine
- Published
- 2014-08-31
- Volume
- 20
- Issue
- 9
- Pages
- 1027-1034
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4159407
- OpenAlex
- W2082020673
- Cited by
- 268
- References
- 32
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 15 · 2023: 17 · 2022: 19 · 2021: 21 · 2020: 18 · 2019: 19 · 2018: 34 · 2017: 38 · 2016: 32 · 2015: 42 · 2014: 3
- FWCI
- 30.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- PubMed Central (acceptedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (25861342)
- National Cancer Institute (R01CA166480, K12-CA9060625, CA163896, R01CA122794, R01CA121210, P01CA129243, R01CA140594, CA 140594, CA90949, CA 122794, P01CA154303, CA154303, P50CA090949, R01CA163896, K12CA090625, P30CA068485, CA 166480)
- U.S. National Library of Medicine (R01LM011177)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- IGF-1 receptor, crizotinib, tyrosine kinase inhibitor resistance, IRS-1, dual kinase inhibition, therapeutic synergy, acquired drug resistance
- MeSH terms
- Crizotinib, Anaplastic Lymphoma Kinase, Female, Humans, Lung Neoplasms, Middle Aged, Pyrazoles, Pyridines, Up-Regulation, Receptor, IGF Type 1, Receptor Protein-Tyrosine Kinases, Insulin Receptor Substrate Proteins, Gene Knockdown Techniques
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