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Targeting Src in endometriosis-associated ovarian cancer
R Manek1, E Pakzamir1, P Mhawech-Fauceglia2
1Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
Abstract:
The SRC proto-oncogene is commonly overexpressed or activated during cancer development. Src family kinase inhibitors are approved for the treatment of certain leukemias, and are in clinical trials for the treatment of solid tumors. Src signaling is activated in endometriosis, a precursor of clear cell and endometrioid subtypes of epithelial ovarian cancers (OCs). We examined the expression of phosphorylated Src (Src-pY416) in 381 primary OC tissues. Thirty-six percent of OCs expressed Src-pY416. Src-pY416 expression was most common in endometriosis-associated OCs (EAOCs) (P=0.011), particularly in clear cell OCs where 58.5% of cases expressed Src-pY416. Src-pY416 expression was associated with shorter overall survival (log rank P=0.002). In vitro inhibition of Src signaling using 4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine (PP2) resulted in reduced anchorage-independent and -dependent growth, and in three-dimensional cell culture models PP2 disrupted aggregate formation in Src-pY416-positive but not in Src-pY416-negative cell lines. These data suggest that targeting active Src signaling could be a novel therapeutic opportunity for EAOCs, and support the further pre-clinical investigation of Src family kinase inhibitors for treating OCs expressing Src-pY416.
Insights
Active Src signaling, a marker in ovarian cancers (OCs), is linked to poorer survival. Targeting this pathway with inhibitors like PP2 shows promise, especially for endometriosis-associated OCs.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- The SRC proto-oncogene is frequently implicated in cancer development.
- Src signaling is activated in endometriosis, a precursor to clear cell and endometrioid ovarian cancers (OCs).
- Src family kinase inhibitors are clinically used for leukemias and investigated for solid tumors.
Purpose of the Study:
- To investigate the expression of phosphorylated Src (Src-pY416) in primary ovarian cancers.
- To determine the association of Src-pY416 expression with OC subtypes, endometriosis association, and patient survival.
- To evaluate the therapeutic potential of inhibiting Src signaling in OC models.
Main Methods:
- Analysis of Src-pY416 expression in 381 primary OC tissues.
- Correlation of Src-pY416 expression with clinicopathological features and survival data.
- In vitro assessment of Src inhibition using PP2 on OC cell growth and aggregate formation.
Main Results:
- 36% of OCs expressed Src-pY416.
- Src-pY416 expression was significantly higher in endometriosis-associated OCs (EAOCs), particularly clear cell subtypes (58.5%).
- Src-pY416 expression correlated with shorter overall survival (P=0.002).
- PP2 treatment reduced OC cell growth and disrupted aggregate formation in Src-pY416-positive cell lines.
Conclusions:
- Active Src signaling is prevalent in a subset of OCs, especially EAOCs.
- Targeting active Src signaling represents a potential therapeutic strategy for EAOCs.
- Further pre-clinical studies of Src family kinase inhibitors are warranted for OCs expressing Src-pY416.
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