title: The mechanisms of differential sensitivity to an insulin-like growth factor-1 receptor inhibitor (BMS-536924) and rationale for combining with EGFR/HER2 inhibitors.
abstract: 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.
authors.affiliation: Bristol-Myers Squibb Company, Princeton, NJ 08543, USA. fei.huang@bms.com
authors.forename: Fei
authors.initials: F
authors.lastname: Huang
authors.forename: Ann
authors.initials: A
authors.lastname: Greer
authors.forename: Warren
authors.initials: W
authors.lastname: Hurlburt
authors.forename: Xia
authors.initials: X
authors.lastname: Han
authors.forename: Rameh
authors.initials: R
authors.lastname: Hafezi
authors.forename: Gayle M
authors.initials: GM
authors.lastname: Wittenberg
authors.forename: Karen
authors.initials: K
authors.lastname: Reeves
authors.forename: Jiwen
authors.initials: J
authors.lastname: Chen
authors.forename: Douglas
authors.initials: D
authors.lastname: Robinson
authors.forename: Aixin
authors.initials: A
authors.lastname: Li
authors.forename: Francis Y
authors.initials: FY
authors.lastname: Lee
authors.forename: Marco M
authors.initials: MM
authors.lastname: Gottardis
authors.forename: Edwin
authors.initials: E
authors.lastname: Clark
authors.forename: Lee
authors.initials: L
authors.lastname: Helman
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Attar
authors.forename: Ashok
authors.initials: A
authors.lastname: Dongre
authors.forename: Joan M
authors.initials: JM
authors.lastname: Carboni
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011728:Pyridones / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D012509:Sarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D001562:Benzimidazoles; D066246:ErbB Receptors; D011728:Pyridones; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; C504983:BMS 536924