MET is highly expressed at different stages of neoplas selleck screening library tic progression and Inhibitors,Modulators,Libraries capable of inducing the proliferation of ovarian cancer cells. Several studies confirmed the important role of HGF/MET signaling in the trans formation of surface ovarian epithelial cells and in the growth and dissemination of Inhibitors,Modulators,Libraries ovarian cancer. Blocking the MET signaling by the MET inhibitors, PF 2341066, or by specific MET RNAi had antiproliferative effects and reduced tumor metastasis in ovarian cancer cells, possibly by suppressing MET dependent PI3 K/ AKT and RAF/MAPK signaling pathways. In our present study, PHA 665752, a MET inhibitor, had mild effect in OVCA429 cell viability, and PHA 665752 inhibition of viability did not correlate with baseline MET tyrosine phosphorylation in ovarian can cer.

Similarly, only a mild effect on ovarian cancer viability were detected after gefitinib mediated EGFR inhibition and Inhibitors,Modulators,Libraries the cell death did not correlate with baseline EGFR tyrosine phosphorylation, in spite of strong EGFR expression in many ovarian cancers. Our findings are in consistent with the lack of effi cacy of gefitinib or erlotinib in ovarian cancer clinical trials. The combination inhibition of EGFR and MET by gefitinib and PHA665752 had similar anti proliferative effects to the inhibition by each of RTKs. AXL is another receptor tyrosine kinase known to be involved in ovarian cancers. AXL promoted proliferation in glioma cells and breast cancer cells, and AXL upregulation and activation was detected in ovarian cancers over normal ovaries.

Our studies showed that AXL knockdown by RNA interference inhibited cell proliferation by 65% in OVCA429 cells, and the combination inhibition of EGFR, MET, and AXL inhibition resulted in 75% decrease in cell viability. HSP90 inhibition has shown anti proliferative effects against ovarian preclinical models, however, the molecular mechanisms are unclear. Our studies show that Inhibitors,Modulators,Libraries multiple receptor tyrosine kinases are co activated Inhibitors,Modulators,Libraries in individual ovarian cancer cells. The HSP90 inhibition led to the dephosphorylation and degradation of EGFR, ERBB2, ERBB4, MET and AXL in various ovarian can cer cells. Our studies showed that the phosphorylated forms of the RTKs were more sensitive to HSP90 inhibi tor mediated degradation. Many protein kinases are degraded by a phosphorylation dependent ubiquitin proteasome system. CDC37, a co chaperone of HSP90, stabilizes client pro teins following their interaction with HSP90 and regu lates protein kinase activity. Treatment with HSP90 inhibitors such as 17 AAG or AUY922 led to UPS dependent degradation of activated RTKs and total obviously RTKs in a time dependent manner, as those seen in GISTs and mesothelioma with HSP90 inhibition. Moser C, et al.