title: Efficacy of the multi-kinase inhibitor enzastaurin is dependent on cellular signaling context.
abstract: The number of targeted small molecules being developed in oncology is increasing rapidly. Many of these are designed to inhibit multiple kinases, and thus the mechanisms of responsiveness and predictive biomarkers can be difficult to discern. In fact, with few exceptions, multi-kinase inhibitors are developed with limited mechanism-based patient selection. Enzastaurin is a multi-kinase inhibitor being studied in several malignancies that we hypothesized would be active in squamous cell carcinoma of the head and neck, because it inhibits classic and novel protein kinase C isoforms. Indeed, enzastaurin reduced the growth of SQ-20B and CAL27 tumor xenografts, decreased proliferation in these cell lines, inhibited putative target phosphorylation, and induced cell cycle arrest. Gene expression arrays confirmed that expression of cell cycle genes, including cyclins D and E, were significantly altered by exposure to enzastaurin. However, testing a panel of squamous cell carcinoma of the head and neck cell lines revealed variable sensitivity to enzastaurin, which correlated significantly with baseline cyclin D1 protein expression. Moreover, sensitivity and resistance could be reversed, respectively, by expression or depletion of cyclin D1. Furthermore, analysis of sensitive and resistant cell lines revealed distinct differences in cyclin D1 regulation. Enzastaurin modulated cyclin D1 synthesis through an Akt-regulated pathway in the former, whereas high-level CCND1 gene amplification was present in the latter. These results underscore the critical relevance of cellular signaling context in developing cancer therapies in general and suggest that enzastaurin in particular would be most effective in tumors where baseline cyclin D1 expression is low to moderate and physiologically regulated.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Kuo
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Helena
authors.initials: H
authors.lastname: Mauceri
authors.forename: Everett E
authors.initials: EE
authors.lastname: Vokes
authors.forename: Ralph
authors.initials: R
authors.lastname: Weichselbaum
authors.forename: Marsha Rich
authors.initials: MR
authors.lastname: Rosner
authors.forename: Ezra Eddy Wyssam
authors.initials: EE
authors.lastname: Cohen
mesh_terms: D000818:Animals; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000473:pathology; D002453:Cell Cycle; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics; D017931:DNA Primers; D005260:Female; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects*; D014183:Transplantation, Heterologous
chemical_list: D017931:DNA Primers; D007211:Indoles; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D019938:Cyclin D1; D051057:Proto-Oncogene Proteins c-akt; C504878:enzastaurin