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

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] Introduction The insulin-like growth factor (IGF) axis plays an essential role in regulating cellular growth, differentiation, apoptosis, tumor angiogenesis, and metastasis and in conferring radioresistance and multiple drug resistance (1). It is a complex multifactorial system consisting of ligands, receptors, and IGF-binding proteins (IGFBPs). Under normal physiologic conditions, the balance between the expression and activities of these molecules is tightly controlled; changes in this delicate balance may trigger a cascade of molecular events that can ultimately lead to malignancy (2). Binding of its ligands to IGF-I receptor (IGF-IR) initiates a cascade of events leading to activation of mitogenic signaling pathways [Ras/Raf/ mitogen-activated protein kinase (MAPK)] and antiapoptotic/ survival pathways (PI3K-Akt/mTor), resulting in proliferation, transformation and survival in tumor cells (3, 4). IGF-IR overexpression and/or enhanced activity has been observed in diverse tumor types, suggesting the potential therapeutic use of agents targeting this pathway may be broad. Various drug discovery approaches, including monoclonal antibody, small molecule inhibitor, antisense, IGF-I peptide mimetic, and dominant-negative mutants that lack enzyme activity have been explored in recent years to modulate the function of IGF-IR and reverse the malignant phenotype in tumor cells (5, 6). Sarcomas and neuroblastomas are areas of highly unmet medical needs. Due to aggressive local behavior and high metastatic propensity, survival rates of these rare cancers are disappointingly low with multimodal treatments and very aggressive chemotherapeutic regimens. IGF-IR and its ligands undergo autocrine/ paracrine regulatory responses, which are important growth regulators in sarcomas (7–10). Inhibition of IGF-IR by antibodies or small molecules, either alone or in combination with other chemotherapeutic agents, has shown antitumor activity in sarcomas (11–13). IGF-IR and insulin receptor are structurally and functionally related and can form heterotetrameric receptors. Insulin receptor activates signaling pathways similar to IGF-IR and has been implicated in human cancers (14, 15). In addition to IGF-IR, preclinical data support an important role for insulin receptor in regulating IGF action, either as a hybrid or holoreceptor (16). Increased insulin sensitivity in breast cancer was observed when targeting IGF-IR (17). Agents targeting all of the receptors responsible for IGF signaling may be necessary to disrupt the malignant phenotype regulated by this growth factor receptor family. BMS-536924, a small molecule inhibitor potent against both IGF-IR and insulin receptor (18), may not only be an advantage but a prerequisite in treating cancers. BMS-536924 showed antitumor Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Current address for G.M. Wittenberg: Siemens Corporate Research, Integrated Data Systems, 755 College Road, East Princeton, NJ 08540. Current address for R.M. Attar: Oncology Research, Centocor R&D, 145 King of Prussia, Radnor, PA 19087. 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: [email protected] or Joan Carboni, Bristol-Myers Squibb, P.O. Box 5400, LVL-K1403 Princeton, NJ 08543. Phone: 609-252-3221; Fax: 609-252-6058; E-mail: joan.carboni@ bms.com. I2009 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-08-0835 www.aacrjournals.org 161 Cancer Res 2009; 69: (1). January 1, 2009 Research Article American Association for Cancer Research Copyright © 2009 on February 21, 2013 cancerres.aacrjournals.org Downloaded from DOI:10.1158/0008-5472.CAN-08-0835