This Article Full Text Full Text (PDF) Supplementary Data Correction (v69,p2149) Correction (v69,p2149) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Huang, F. Articles by Carboni, J. M. Search for Related Content PubMed PubMed Citation Articles by Huang, F. Articles by Carboni, J. M.

The Mechanisms of Differential Sensitivity to an Insulin-like Growth Factor-1 Receptor Inhibitor (BMS-536924) and Rationale for Combining with EGFR/HER2 Inhibitors

¹ Bristol-Myers Squibb Company, Princeton, New Jersey and ² Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Fei Huang, Bristol-Myers Squibb, P.O. Box 5400, HW3B-2.02, Princeton, NJ 08543. Phone: 609-818-5303; Fax: 609-818-5839; E-mail: fei.huang{at}bms.com or Joan Carboni, Bristol-Myers Squibb, P.O. Box 5400, LVL-K14-03 Princeton, NJ 08543. Phone: 609-252-3221; Fax: 609-252-6058; E-mail: joan.carboni{at}bms.com.

Key Words: IGF-IR inhibitor • kinase crosstalk • molecular signatures

Overexpression and enhanced activity of insulin-like growth factor-I receptor (IGF-IR) in diverse tumor types make it an attractive target for cancer therapy. BMS-536924 is a potent small molecule inhibitor of IGF-IR, which shows antitumor activity in multiple tumor models, including sarcoma. To facilitate the development of IGF-IR inhibitors as cancer therapy, identification of biomarkers for selecting patients most likely to derive clinical benefit is needed. To do so, 28 sarcoma and neuroblastoma cell lines were screened for in vitro response to BMS-536924 to identify sensitive and resistant cell lines. Notably, Ewing's sarcoma, rhabdomyosarcoma, and neuroblastoma are more responsive to BMS-536924, suggesting these specific subtypes may represent potential targeted patient subpopulations for the IGF-IR inhibitor. Gene expression and protein profiling were performed on these cell lines, and candidate biomarkers correlating with intrinsic and/or acquired resistance to BMS-536924 were identified. IGF-I, IGF-II, and IGF-IR were highly expressed in sensitive cell lines, whereas IGFBP-3 and IGFBP-6 were highly expressed in resistant lines. Overexpression of epidermal growth factor receptor (EGFR) and its ligands in resistant cell lines may represent one possible resistance mechanism by the adaptation of IGF-IR–independent growth using alternative signaling pathways. Based on cross-talk between IGF-IR and EGFR pathways, combination studies to target both pathways were performed, and enhanced inhibitory activities were observed. These results provide a strategy for testing combinations of IGF-IR inhibitors with other targeted therapies in clinical studies to achieve improved patient outcomes. Further exploration of mechanisms for intrinsic and acquired drug resistance by these preclinical studies may lead to more rationally designed drugs that target multiple pathways for enhanced antitumor efficacy. [Cancer Res 2009;69(1):161–70]

This article has been cited by other articles:

				C. P. Carden, L. R. Molife, and J. S. de Bono Predictive biomarkers for targeting insulin-like growth factor-I (IGF-I) receptor Mol. Cancer Ther., August 1, 2009; 8(8): 2077 - 2078. [Full Text] [PDF]

				J. S.P. Yuen, E. Akkaya, Y. Wang, M. Takiguchi, S. Peak, M. Sullivan, A. S. Protheroe, and V. M. Macaulay Validation of the type 1 insulin-like growth factor receptor as a therapeutic target in renal cancer Mol. Cancer Ther., June 1, 2009; 8(6): 1448 - 1459. [Abstract] [Full Text] [PDF]

				Correction: Article on Differential Sensitivity to IGF-IR Inhibitor Cancer Res., March 1, 2009; 69(5): 2149 - 2149. [Full Text] [PDF]