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Preclinical Efficacy for AKT Targeting in Clear Cell Carcinoma of the Ovary
- Source :
- Molecular Cancer Research. 13:795-806
- Publication Year :
- 2015
- Publisher :
- American Association for Cancer Research (AACR), 2015.
-
Abstract
- The aim of this study was to determine the role of AKT as a therapeutic target in ovarian clear cell carcinoma (CCC), an aggressive, chemoresistant histologic subtype of ovarian cancer. AKT activation was assessed by immunohistochemistry (IHC) using human tissue microarrays of primary ovarian cancers, composed of both CCC and serous adenocarcinoma (SAC). The growth-inhibitory effect of AKT-specific targeting by the small-molecule inhibitor, perifosine, was examined using ovarian CCC cell lines in vitro and in vivo. Finally, the activity of perifosine was examined using in CCC-derived tumors that had acquired resistance to anti-VEGF or chemotherapeutics such as bevacizumab or cisplatin, respectively. Interestingly, AKT was frequently activated both in early-stage and advanced-stage CCCs. Treatment of CCC cells with perifosine attenuated the activity of AKT–mTORC1 signaling, inhibited proliferation, and induced apoptosis. The effect of perifosine was more profound under conditions of high AKT activity compared with low AKT activity. Increased AKT activation and enhanced sensitivity to perifosine were observed in the context of cisplatin-resistant CCC. Treatment with perifosine concurrently with cisplatin significantly enhanced the antitumor effect of cisplatin. Moreover, perifosine showed significant antitumor activity in CCC-derived tumors that had acquired resistance to bevacizumab or cisplatin. Collectively, these data reveal that AKT is frequently activated in ovarian CCCs and is a promising therapeutic target in aggressive forms of ovarian cancer. Implications: AKT-targeted therapy has value in a first-line setting as well as a second-line treatment for recurrent disease developing after platinum-based chemotherapy or bevacizumab treatment. Mol Cancer Res; 13(4); 795–806. ©2014 AACR.
- Subjects :
- Cancer Research
Bevacizumab
Phosphorylcholine
Antineoplastic Agents
Context (language use)
Mechanistic Target of Rapamycin Complex 1
Article
Mice
chemistry.chemical_compound
Cell Line, Tumor
medicine
Animals
Humans
Molecular Biology
Protein kinase B
Ovarian Neoplasms
Cisplatin
business.industry
TOR Serine-Threonine Kinases
Cancer
Drug Synergism
Perifosine
medicine.disease
Xenograft Model Antitumor Assays
Oncology
chemistry
Drug Resistance, Neoplasm
Multiprotein Complexes
Clear cell carcinoma
Cancer research
Female
business
Ovarian cancer
Proto-Oncogene Proteins c-akt
Adenocarcinoma, Clear Cell
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 15573125 and 15417786
- Volume :
- 13
- Database :
- OpenAIRE
- Journal :
- Molecular Cancer Research
- Accession number :
- edsair.doi.dedup.....9ac65f029d0964e81d48bcc0a403214a