title: Combinatorial efficacy achieved through two-point blockade within a signaling pathway-a chemical genetic approach.
abstract: Whether the apparent efficacy of a specific kinase inhibitor is attributable solely to inhibition of its primary target, or to combined inhibition of additional unidentified kinases, is a critical issue in cancer therapy. We used a chemical genetic approach to generate a selective inhibitor of v-erbB [a transforming allele of epidermal growth factor receptor (EGFR)] and interrogated inhibition in known downstream signaling pathways. On the basis of this analysis, we hypothesized that dual inhibition of v-erbB and phosphatidylinositol 3' (PI3) kinases could show improved potency. We, therefore, used two different cell lines to examine the effects of v-erbB or EGFR inhibitors, in combination with PI3 kinase inhibitors, in mouse models for EGFR-driven cancers. When treated with NaPP1, v-erbB-as1-transformed fibroblasts showed cell-cycle arrest and decreased activity of Akt kinase. Inhibitors of v-erbB-as1 and of PI3 kinase showed enhanced efficacy in treating established 3T3:v-erbB-as1 tumor allografts. We extended these results to the human glioma cell line U87:MG transduced with DeltaEGFR, a tumor-derived activated allele, treating tumor-bearing mice with vehicle, the EGFR inhibitor ZD1839, LY294002, or ZD1839 plus LY294002. In human glioma xenografts, inhibition of EGFR cooperated similarly with inhibition of PI3 kinase. Our experiments provide a preclinical mechanistic basis for combining biologically based therapies directed against two targets within a complex signaling cascade.
authors.affiliation: Department of Neurology, University of California, San Francisco, California 94143-0663, USA.
authors.forename: Qi-Wen
authors.initials: QW
authors.lastname: Fan
authors.forename: Kimberly Musa
authors.initials: KM
authors.lastname: Specht
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Dmitriy D
authors.initials: DD
authors.lastname: Goldenberg
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D000077156:Gefitinib; D005910:Glioma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells; D009281:Naphthalenes / Q000494:pharmacology; D018739:Oncogene Proteins v-erbB / Q000037:antagonists & inhibitors* / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D018739:Oncogene Proteins v-erbB; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib