Combinatorial efficacy achieved through two-point blockade within a signaling pathway-a chemical genetic approach.
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.[1]References
- Combinatorial efficacy achieved through two-point blockade within a signaling pathway-a chemical genetic approach. Fan, Q.W., Specht, K.M., Zhang, C., Goldenberg, D.D., Shokat, K.M., Weiss, W.A. Cancer Res. (2003) [Pubmed]
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