Preclinical Efficacy for AKT Targeting in Clear Cell Carcinoma of the Ovary.

Abstract

UNLABELLED:

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.

• Authors: Tomoyuki Sasano, Seiji Mabuchi, Hiromasa Kuroda, Mahiru Kawano, Yuri Matsumoto, Ryoko Takahashi, Takeshi Hisamatsu, Kenjiro Sawada, Kae Hashimoto, Aki Isobe, Joseph R Testa, Tadashi Kimura
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 13 Issue 4 Pg. 795-806 (Apr 2015) ISSN: 1557-3125 [Electronic] United States
• PMID: 25519148 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Multiprotein Complexes
• Phosphorylcholine
• perifosine
• AKT1 protein, human
• Mechanistic Target of Rapamycin Complex 1
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Cisplatin

Topics

• Adenocarcinoma, Clear Cell (drug therapy, metabolism)
• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cisplatin (administration & dosage, pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Female
• Humans
• Mechanistic Target of Rapamycin Complex 1
• Mice
• Multiprotein Complexes (metabolism)
• Ovarian Neoplasms (drug therapy, metabolism)
• Phosphorylcholine (administration & dosage, analogs & derivatives, pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)
• Xenograft Model Antitumor Assays