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Clin Cancer Res. 2018 Oct 1;24(19):4874-4886. doi: 10.1158/1078-0432.CCR-17-3697. Epub 2018 Jun 29.

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

Simpkins F1,2,3, Jang K#4,5, Yoon H#4, Hew KE#4,2, Kim M4,5, Azzam DJ4,5, Sun J4, Zhao D4, Ince TA4,6,7, Liu W8, Guo W8, Wei Z9, Zhang G10, Mills GB8, Slingerland JM1,5,11.

Author information

1
Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida. jslingerland@med.miami.edu Fiona.simpkins@uphs.upenn.edu.
2
Department of Obstetrics & Gynecology, University of Miami, Miami, Florida.
3
Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics & Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania.
4
Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.
5
Department of Biochemistry and Molecular Biology, University of Miami, Miami, Florida.
6
Department of Pathology and Laboratory Medicine, University of Miami, Miami, Florida.
7
Interdisciplinary Stem Cell Institute, University of Miami, Miami, Florida.
8
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
9
Department of Computer Science, New Jersey Institute of Technology, Newark, New Jersey.
10
Wistar Institute, Philadelphia, Pennsylvania.
11
Department of Medicine, University of Miami, Miami, Florida.
#
Contributed equally

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.

PMID:
29959144
PMCID:
PMC6557165
[Available on 2019-10-01]
DOI:
10.1158/1078-0432.CCR-17-3697

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