Dual Src and MEK inhibition decreases ovarian cancer growth and targets tumor initiating stem-like cells
Document Type
Article
Publication Date
10-1-2018
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 ALDH1þ 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.
Identifier
85054062146 (Scopus)
Publication Title
Clinical Cancer Research
External Full Text Location
https://doi.org/10.1158/1078-0432.CCR-17-3697
e-ISSN
15573265
ISSN
10780432
PubMed ID
29959144
First Page
4874
Last Page
4886
Issue
19
Volume
24
Grant
K08 CA151892-01
Fund Ref
National Cancer Institute
Recommended Citation
Simpkins, Fiona; Jang, Kibeom; Yoon, Hyunho; Hew, Karina E.; Kim, Minsoon; Azzam, Diana J.; Sun, Jun; Zhao, Dekuang; Ince, Tan A.; Liu, Wenbin; Guo, Wei; Wei, Zhi; Zhang, Gao; Mills, Gordon B.; and Slingerland, Joyce M., "Dual Src and MEK inhibition decreases ovarian cancer growth and targets tumor initiating stem-like cells" (2018). Faculty Publications. 8365.
https://digitalcommons.njit.edu/fac_pubs/8365
