Targeting HSP90 in ovarian cancers with multiple receptor tyrosine kinase coactivation.

Yisheng Jiao,Fanguo Meng,Aiyuan Wang,Wenbin Ou,Haimeng Zhou

doi:10.1186/1476-4598-10-125

Yisheng Jiao, Fanguo Meng + Show 3 more

Open Access

https://doi.org/10.1186/1476-4598-10-125

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Journal: Molecular Cancer	Publication Date: Jan 1, 2011
Citations: 82	License type: cc-by

Affiliation: China Medical University, Tsinghua University

Abstract

BackgroundOvarian cancer has the highest mortality rate of all gynecologic malignancy. The receptor tyrosine kinases (RTKs), including EGFR, ERBB2, PDGFR, VEGFR and MET, are activated in subsets of ovarian cancer, suggesting that these kinases might represent novel therapeutic targets. However, clinical trials have not or just partially shown benefit to ovarian cancers treated with EGFR, ERBB2, or PDGFR inhibitors. Despite multiple RTK activation in ovarian cancer pathogenesis, it is unclear whether transforming activity is dependent on an individual kinase oncoprotein or the coordinated activity of multiple kinases. We hypothesized that a coordinated network of multi-RTK activation is important for the tumorigenesis of ovarian cancers.ResultsHerein, we demonstrate co-activation of multiple RTKs (EGFR, ERBB2, ERBB4, MET and/or AXL) in individual ovarian cancer cell lines and primary tumors. We also show that coordinate inhibition of this multi-kinase signaling has substantially greater effect on ovarian cancer proliferation and survival, compared to inhibition of individual activated kinases. The inhibition of this multi-RTK signaling by HSP90 suppression results in profound pro-apoptotic and anti-proliferative effects, and is associated with the inactivation of RTK downstream PI3-K/AKT/mTOR and RAF/MAPK signaling.ConclusionThese studies suggest that anti-multiple RTK strategy could be useful in the treatment of ovarian cancer.

Highlights

Ovarian cancer has the highest mortality rate of all gynecologic malignancy
The increasing evidences suggest that receptor tyrosine kinase (RTK) activation participates in the oncogenic progression from nonneoplastic mesothelial lining of the ovaries or the fallopian tube epithelium to epithelial ovarian cancer
Expression and activation of multiple RTKs in ovarian cancer cells By phospho-RTK assays, the expression and activation of Epidermal growth factor receptor (EGFR), ERBB2, ERBB4 and MET were activated in SKOV3 cells, and EGFR, MET and AXL in OVCA429 cells, and EGFR in ES2 cells under serum starved medium condition (Figure 1)

Summary

Introduction

The receptor tyrosine kinases (RTKs), including EGFR, ERBB2, PDGFR, VEGFR and MET, are activated in subsets of ovarian cancer, suggesting that these kinases might represent novel therapeutic targets. The increasing evidences suggest that receptor tyrosine kinase (RTK) activation participates in the oncogenic progression from nonneoplastic mesothelial lining of the ovaries or the fallopian tube epithelium to epithelial ovarian cancer. EGFR upregulation is detected in ~60% ovarian cancer and associated with increased tumor cell proliferation, advanced tumor grades and poor patient prognosis [6,7]. EPHA2 inhibition by dasatinib or a novel immunoconjugate containing an anti-EPHA2 monoclonal antibody linked to a chemotherapeutic agent, shows antitumor activity against EPHA2-positive ovarian cancer cell lines and mouse tumor models [15,16]. The AXL receptor tyrosine kinase protein, and its ligand Gas 6 (growth arrest-specific gene 6) are expressed significantly higher in ovarian cancers than in normal ovaries, its role in the tumorigenesis of ovarian cancer needs further studies [22]

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