title: Dual mitogen-activated protein kinase and epidermal growth factor receptor inhibition in biliary and pancreatic cancer.
abstract: This study aimed to develop rational combinations of targeted agents against biliary and pancreatic cancers. To this end, we compared the global gene expression profile of biliary cancer cell lines with different degrees of sensibility to the epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib using the Affymetrix U133A microarray platform. A set of 32 genes, including genes involved in signal transduction pathways, cell cycle regulation, and angiogenesis, was highly overexpressed in resistant cells. Five of these genes encoded proteins in the Ras/Raf/mitogen-activated protein kinase (MAPK) pathway, a finding that was confirmed by Western blot and immunohistochemistry. Gefitinib failed to inhibit the MAPK pathway in resistant cell lines. Based on these data, we explored the activity of dual treatment with gefitinib in combination with CI-1040, a MAPK inhibitor. This strategy effectively resulted in inhibition of the MAPK signaling pathway and exerted antitumor effects in vitro and in vivo in tumors resistant to each of the agents alone. To further confirm these results, we tested the combined treatment in four tumor xenografts generated from patients with resected pancreatic cancer. Combined treatment was more effective than either single agent alone in this model. This study illustrates the value of global analysis of gene expression to rationally design combinations of mechanistic-based drugs. In addition, the data support the efficacy of combined epidermal growth factor receptor and MAPK inhibitors in biliary and pancreatic cancers, providing the basis to test this combination in the clinic.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, School of Medicine, The Johns Hopkins University, The Baunting and Blaustein Cancer Research Building, 1650 Orleans Street, Room 1M89, Baltimore, MD 21231, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.forename: Belen
authors.initials: B
authors.lastname: Rubio-Viqueira
authors.forename: Maria L
authors.initials: ML
authors.lastname: Amador
authors.forename: Victor
authors.initials: V
authors.lastname: Grunwald
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: Christine
authors.initials: C
authors.lastname: Iacobuzio-Donahue
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use; D001661:Biliary Tract Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D001549:Benzamides; D014408:Biomarkers, Tumor; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D000077156:Gefitinib