This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 Haluska, P. Articles by Erlichman, C. Search for Related Content PubMed PubMed Citation Articles by Haluska, P. Articles by Erlichman, C.

In vitro and In vivo Antitumor Effects of the Dual Insulin-Like Growth Factor-I/Insulin Receptor Inhibitor, BMS-554417

Divisions of ¹ Medical Oncology, ² Developmental Oncology Research, and ³ Endocrinology and Metabolism, Mayo Clinic College of Medicine, Rochester, Minnesota; ⁴ Oncology Drug Discovery, Pharmaceutical Research Institute, Bristol-Myers Squibb Co., Princeton, New Jersey; and ⁵ Discovery Chemistry, Bristol-Myers Squibb Co., Wallingford, Connecticut

Requests for reprints: Charles Erlichman, Division of Medical Oncology, Guggenheim 1311, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-284-3514; Fax: 507-266-5146; E-mail: erlichman.charles{at}mayo.edu.

The insulin-like growth factor receptor (IGF-IR) and insulin receptor are either overactivated and/or overexpressed in a wide range of tumor types and contribute to tumorigenicity, proliferation, metastasis, and drug resistance. Here, we show that BMS-554417, a novel small molecule developed as an inhibitor of IGF-IR, inhibits IGF-IR and insulin receptor kinase activity and proliferation in vitro, and reduces tumor xenograft size in vivo. In a series of carcinoma cell lines, the IC₅₀ for proliferation ranged from 120 nmol/L (Colo205) to >8.5 µmol/L (OV202). The addition of stimulatory ligands was unnecessary for the antiproliferative effect in MCF-7 and OV202 cells. BMS-554417 treatment inhibited IGF-IR and insulin receptor signaling through extracellular signal-related kinase as well as the phosphoinositide 3-kinase/Akt pathway, as evidenced by decreased Akt phosphorylation at Ser⁴⁷³. At doses that inhibited proliferation, the compound also caused a G₀-G₁ arrest and prevented nuclear accumulation of cyclin D1 in response to LR3 IGF-I. In Jurkat T-cell leukemia cells, this agent triggered apoptotic cell death via the mitochondrial pathway. BMS-554417 was orally bioavailable and significantly inhibited the growth of IGF1R-Sal tumor xenografts in vivo. BMS-554417 is a member of a novel class of IGF-IR/insulin receptor inhibitors that have potential clinical applications because of their antiproliferative and proapoptotic activity in vitro and in vivo. (Cancer Res 2006; 66(1): 362-71)

This article has been cited by other articles:

				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]

				P. Sabbatini, J. L. Rowand, A. Groy, S. Korenchuk, Q. Liu, C. Atkins, M. Dumble, J. Yang, K. Anderson, B. J. Wilson, et al. Antitumor Activity of GSK1904529A, a Small-molecule Inhibitor of the Insulin-like Growth Factor-I Receptor Tyrosine Kinase Clin. Cancer Res., May 1, 2009; 15(9): 3058 - 3067. [Abstract] [Full Text] [PDF]

				M.-C. Crouthamel, J. A. Kahana, S. Korenchuk, S.-Y. Zhang, G. Sundaresan, D. J. Eberwein, K. K. Brown, and R. Kumar Mechanism and Management of AKT Inhibitor-Induced Hyperglycemia Clin. Cancer Res., January 1, 2009; 15(1): 217 - 225. [Abstract] [Full Text] [PDF]

				B. C. Litzenburger, H.-J. Kim, I. Kuiatse, J. M. Carboni, R. M. Attar, M. M. Gottardis, C. R. Fairchild, and A. V. Lee BMS-536924 Reverses IGF-IR-Induced Transformation of Mammary Epithelial Cells and Causes Growth Inhibition and Polarization of MCF7 Cells Clin. Cancer Res., January 1, 2009; 15(1): 226 - 237. [Abstract] [Full Text] [PDF]

				J. H. Law, G. Habibi, K. Hu, H. Masoudi, M. Y.C. Wang, A. L. Stratford, E. Park, J. M.W. Gee, P. Finlay, H. E. Jones, et al. Phosphorylated Insulin-Like Growth Factor-I/Insulin Receptor Is Present in All Breast Cancer Subtypes and Is Related to Poor Survival Cancer Res., December 15, 2008; 68(24): 10238 - 10246. [Abstract] [Full Text] [PDF]

				M. M. Chitnis, J. S.P. Yuen, A. S. Protheroe, M. Pollak, and V. M. Macaulay The Type 1 Insulin-Like Growth Factor Receptor Pathway Clin. Cancer Res., October 15, 2008; 14(20): 6364 - 6370. [Abstract] [Full Text] [PDF]

				J. Rodon, V. DeSantos, R. J. Ferry Jr., and R. Kurzrock Early drug development of inhibitors of the insulin-like growth factor-I receptor pathway: Lessons from the first clinical trials Mol. Cancer Ther., September 1, 2008; 7(9): 2575 - 2588. [Abstract] [Full Text] [PDF]

				Y. Shang, Y. Mao, J. Batson, S. J. Scales, G. Phillips, M. R. Lackner, K. Totpal, S. Williams, J. Yang, Z. Tang, et al. Antixenograft tumor activity of a humanized anti-insulin-like growth factor-I receptor monoclonal antibody is associated with decreased AKT activation and glucose uptake Mol. Cancer Ther., September 1, 2008; 7(9): 2599 - 2608. [Abstract] [Full Text] [PDF]

				P. Haluska, J. M. Carboni, C. TenEyck, R. M. Attar, X. Hou, C. Yu, M. Sagar, T. W. Wong, M. M. Gottardis, and C. Erlichman HER receptor signaling confers resistance to the insulin-like growth factor-I receptor inhibitor, BMS-536924 Mol. Cancer Ther., September 1, 2008; 7(9): 2589 - 2598. [Abstract] [Full Text] [PDF]

				W. Piao, Y. Wang, Y. Adachi, H. Yamamoto, R. Li, A. Imsumran, H. Li, T. Maehata, M. Ii, Y. Arimura, et al. Insulin-like growth factor-I receptor blockade by a specific tyrosine kinase inhibitor for human gastrointestinal carcinomas Mol. Cancer Ther., June 1, 2008; 7(6): 1483 - 1493. [Abstract] [Full Text] [PDF]

				M. Lajous, M.-C. Boutron-Ruault, A. Fabre, F. Clavel-Chapelon, and I. Romieu Carbohydrate intake, glycemic index, glycemic load, and risk of postmenopausal breast cancer in a prospective study of French women Am. J. Clinical Nutrition, May 1, 2008; 87(5): 1384 - 1391. [Abstract] [Full Text] [PDF]

				D. Sachdev and D. Yee Disrupting Insulin-Like Growth Factor Signaling as a Potential Cancer Therapy Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 39 - 58. [Abstract] [Full Text] [PDF]

				P. D. Ryan and P. E. Goss The Emerging Role of the Insulin-Like Growth Factor Pathway as a Therapeutic Target in Cancer Oncologist, January 1, 2008; 13(1): 16 - 24. [Abstract] [Full Text] [PDF]

				G Hudelist, T Wagner, M Rosner, A Fink-Retter, D Gschwantler-Kaulich, K Czerwenka, R Kroiss, M Tea, K Pischinger, W J Kostler, et al. Intratumoral IGF-I protein expression is selectively upregulated in breast cancer patients with BRCA1/2 mutations Endocr. Relat. Cancer, December 1, 2007; 14(4): 1053 - 1062. [Abstract] [Full Text] [PDF]

				P. Haluska, H. M. Shaw, G. N. Batzel, D. Yin, J. R. Molina, L. R. Molife, T. A. Yap, M. L. Roberts, A. Sharma, A. Gualberto, et al. Phase I Dose Escalation Study of the Anti Insulin-Like Growth Factor-I Receptor Monoclonal Antibody CP-751,871 in Patients with Refractory Solid Tumors Clin. Cancer Res., October 1, 2007; 13(19): 5834 - 5840. [Abstract] [Full Text] [PDF]

				Q.-s. Ji, M. J. Mulvihill, M. Rosenfeld-Franklin, A. Cooke, L. Feng, G. Mak, M. O'Connor, Y. Yao, C. Pirritt, E. Buck, et al. A novel, potent, and selective insulin-like growth factor-I receptor kinase inhibitor blocks insulin-like growth factor-I receptor signaling in vitro and inhibits insulin-like growth factor-I receptor dependent tumor growth in vivo Mol. Cancer Ther., August 1, 2007; 6(8): 2158 - 2167. [Abstract] [Full Text] [PDF]

				H. Zhang, A. M. Pelzer, D. T. Kiang, and D. Yee Down-regulation of Type I Insulin-like Growth Factor Receptor Increases Sensitivity of Breast Cancer Cells to Insulin Cancer Res., January 1, 2007; 67(1): 391 - 397. [Abstract] [Full Text] [PDF]

				D. Sachdev and D. Yee Disrupting insulin-like growth factor signaling as a potential cancer therapy Mol. Cancer Ther., January 1, 2007; 6(1): 1 - 12. [Abstract] [Full Text] [PDF]

				J Riedemann and V M Macaulay IGF1R signalling and its inhibition Endocr. Relat. Cancer, December 1, 2006; 13(Supplement_1): S33 - S43. [Abstract] [Full Text] [PDF]

				E. Buck, A. Eyzaguirre, E. Brown, F. Petti, S. McCormack, J. D. Haley, K. K. Iwata, N. W. Gibson, and G. Griffin Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small-cell lung, pancreatic, colon, and breast tumors. Mol. Cancer Ther., November 1, 2006; 5(11): 2676 - 2684. [Abstract] [Full Text] [PDF]

				B. Davidson, Z. Zhang, L. Kleinberg, M. Li, V. A. Florenes, T.-L. Wang, and I.-M. Shih Gene expression signatures differentiate ovarian/peritoneal serous carcinoma from diffuse malignant peritoneal mesothelioma. Clin. Cancer Res., October 15, 2006; 12(20): 5944 - 5950. [Abstract] [Full Text] [PDF]