Dual Src and MEK Inhibition Decreases Ovarian Cancer Growth and Targets Tumor Initiating Stem-Like Cells.

Abstract

Purpose: Rational targeted therapies are needed for treatment of ovarian cancers. Signaling kinases Src and MAPK are activated in high-grade serous ovarian cancer (HGSOC). Here, we tested the frequency of activation of both kinases in HGSOC and the therapeutic potential of dual kinase inhibition.Experimental Design: MEK and Src activation was assayed in primary HGSOC from The Cancer Genome Atlas (TGGA). Effects of dual kinase inhibition were assayed on cell-cycle, apoptosis, gene, and proteomic analysis; cancer stem cells; and xenografts.Results: Both Src and MAPK are coactivated in 31% of HGSOC, and this associates with worse overall survival on multivariate analysis. Frequent dual kinase activation in HGSOC led us to assay the efficacy of combined Src and MEK inhibition. Treatment of established lines and primary ovarian cancer cultures with Src and MEK inhibitors saracatinib and selumetinib, respectively, showed target kinase inhibition and synergistic induction of apoptosis and cell-cycle arrest in vitro, and tumor inhibition in xenografts. Gene expression and proteomic analysis confirmed cell-cycle inhibition and autophagy. Dual therapy also potently inhibited tumor-initiating cells. Src and MAPK were both activated in tumor-initiating populations. Combination treatment followed by drug washout decreased sphere formation and ALDH1+ cells. In vivo, tumors dissociated after dual therapy showed a marked decrease in ALDH1 staining, sphere formation, and loss of tumor-initiating cells upon serial xenografting.Conclusions: Selumetinib added to saracatinib overcomes EGFR/HER2/ERBB2-mediated bypass activation of MEK/MAPK observed with saracatinib alone and targets tumor-initiating ovarian cancer populations, supporting further evaluation of combined Src-MEK inhibition in clinical trials. Clin Cancer Res; 24(19); 4874-86. ©2018 AACR.

• Authors: Fiona Simpkins, Kibeom Jang, Hyunho Yoon, Karina E Hew, Minsoon Kim, Diana J Azzam, Jun Sun, Dekuang Zhao, Tan A Ince, Wenbin Liu, Wei Guo, Zhi Wei, Gao Zhang, Gordon B Mills, Joyce M Slingerland
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 24 Issue 19 Pg. 4874-4886 (10 01 2018) ISSN: 1557-3265 [Electronic] United States
• PMID: 29959144 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• AZD 6244
• Benzimidazoles
• Benzodioxoles
• Estrogen Receptor alpha
• Protein Kinase Inhibitors
• Quinazolines
• saracatinib
• src-Family Kinases
• MAP Kinase Kinase 1

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
• Apoptosis (drug effects)
• Benzimidazoles (pharmacology)
• Benzodioxoles (administration & dosage)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease-Free Survival
• Drug Resistance, Neoplasm
• Estrogen Receptor alpha (genetics)
• Female
• Humans
• MAP Kinase Kinase 1 (antagonists & inhibitors, genetics)
• Mice
• Middle Aged
• Neoplastic Stem Cells (drug effects)
• Ovarian Neoplasms (drug therapy, genetics, pathology)
• Protein Kinase Inhibitors (administration & dosage)
• Proteomics
• Quinazolines (administration & dosage)
• Xenograft Model Antitumor Assays
• src-Family Kinases (antagonists & inhibitors, genetics)