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Targeting SRC in mucinous ovarian carcinoma
- Source :
- Clinical cancer research : an official journal of the American Association for Cancer Research. 17(16)
- Publication Year :
- 2011
-
Abstract
- Purpose: Mucinous ovarian carcinomas have a distinct clinical pattern compared with other subtypes of ovarian carcinoma. Here, we evaluated (i) stage-specific clinical significance of mucinous ovarian carcinomas in a large cohort and (ii) the functional role of Src kinase in preclinical models of mucinous ovarian carcinoma. Experimental Design: A total of 1,302 ovarian cancer patients including 122 (9.4%) cases of mucinous carcinoma were evaluated for survival analyses. Biological effects of Src kinase inhibition were tested using dasatinib-based therapy in a novel orthotopic mucinous ovarian cancer model (RMUG-S-ip2). Results: Patients with advanced-stage mucinous ovarian cancer had significantly worse survival than those with serous histology: median overall survival, 1.67 versus 3.41 years, P = 0.002; median survival time after recurrence of 0.53 versus 1.66 years, P < 0.0001. Among multiple ovarian cancer cell lines, RMUG-S-ip2 mucinous ovarian cancer cells showed the highest Src kinase activity. Moreover, oxaliplatin treatment induced phosphorylation of Src kinase. This induced activity by oxaliplatin therapy was inhibited by concurrent administration of dasatinib. Targeting Src with dasatinib in vivo showed significant antitumor effects in the RMUG-S-ip2 model but not in the serous ovarian carcinoma (SKOV3-TR) model. Combination therapy of oxaliplatin with dasatinib further showed significant effects on reducing cell viability, increasing apoptosis, and in vivo antitumor effects in the RMUG-S-ip2 model. Conclusions: Our results suggest that poor survival of women with mucinous ovarian carcinoma is associated with resistance to cytotoxic therapy. Targeting Src kinase with a combination of dasatinib and oxaliplatin may be an attractive approach for this disease. Clin Cancer Res; 17(16); 5367–78. ©2011 AACR.
- Subjects :
- Oncology
Adult
Cancer Research
medicine.medical_specialty
endocrine system diseases
Combination therapy
Organoplatinum Compounds
Cell Survival
Blotting, Western
Dasatinib
Mice, Nude
Antineoplastic Agents
Apoptosis
Kaplan-Meier Estimate
Mice
Internal medicine
Ovarian carcinoma
Cell Line, Tumor
medicine
Mucinous carcinoma
Animals
Humans
Protein Kinase Inhibitors
Aged
Neoplasm Staging
Oligonucleotide Array Sequence Analysis
Ovarian Neoplasms
business.industry
Middle Aged
medicine.disease
Adenocarcinoma, Mucinous
Xenograft Model Antitumor Assays
female genital diseases and pregnancy complications
Oxaliplatin
Gene Expression Regulation, Neoplastic
Serous fluid
Thiazoles
Pyrimidines
src-Family Kinases
Cancer research
Female
Ovarian cancer
business
Proto-oncogene tyrosine-protein kinase Src
medicine.drug
Subjects
Details
- ISSN :
- 15573265
- Volume :
- 17
- Issue :
- 16
- Database :
- OpenAIRE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Accession number :
- edsair.doi.dedup.....7346d45b1a48ed4971992905e4165602