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: Qi-Wen Fan, Kimberly Musa Specht, Chao Zhang, Dmitriy D Goldenberg, Kevan M Shokat, William A Weiss
• Journal: Cancer research (Cancer Res) Vol. 63 Issue 24 Pg. 8930-8 (Dec 15 2003) ISSN: 0008-5472 [Print] United States
• PMID: 14695210 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine
• Enzyme Inhibitors
• Naphthalenes
• Oncogene Proteins v-erbB
• Phosphoinositide-3 Kinase Inhibitors
• Pyrazoles
• Pyrimidines
• Quinazolines
• ErbB Receptors
• Gefitinib

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Brain Neoplasms (drug therapy, enzymology, pathology)
• Cell Division (drug effects, physiology)
• Cell Line, Tumor
• Drug Synergism
• Enzyme Inhibitors (pharmacology)
• ErbB Receptors (antagonists & inhibitors)
• Female
• Gefitinib
• Glioma (drug therapy, enzymology, pathology)
• Humans
• Mice
• Mice, Inbred BALB C
• NIH 3T3 Cells
• Naphthalenes (pharmacology)
• Oncogene Proteins v-erbB (antagonists & inhibitors, genetics)
• Phosphoinositide-3 Kinase Inhibitors
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• Quinazolines (pharmacology)
• Signal Transduction
• Transduction, Genetic
• Xenograft Model Antitumor Assays