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.
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.
Both Src and MAPK are co-activated 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.
Selumetinib added to saracatinib overcomes EGFR/HER2/ERBB2-mediated bypass activation of MEK/MAPK observed with saracatinib alone and targets tumor-initiating OVCA populations, supporting further evaluation of combined Src-MEK inhibition in clinical trials.
Pharmacology, Toxicology and Pharmaceutical Science
4
10%
Agricultural and Biological Sciences
2
5%
Psychology
2
5%
Other
3
7%
Unknown
16
39%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 5. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 08 July 2018.
All research outputs
#10,166,721
of 34,350,842 outputs
Outputs from Clinical Cancer Research
#10,346
of 17,842 outputs
Outputs of similar age
#127,437
of 386,329 outputs
Outputs of similar age from Clinical Cancer Research
#104
of 192 outputs
Altmetric has tracked 34,350,842 research outputs across all sources so far. This one has received more attention than most of these and is in the 70th percentile.
So far Altmetric has tracked 17,842 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 12.3. This one is in the 41st percentile – i.e., 41% of its peers scored the same or lower than it.
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We're also able to compare this research output to 192 others from the same source and published within six weeks on either side of this one. This one is in the 44th percentile – i.e., 44% of its contemporaries scored the same or lower than it.
