Abstract |
Ovarian clear cell carcinoma (OCCC) displays a higher resistance to first line chemotherapy, requiring the development of new therapeutics. We previously identified a frequent chromosomal gain at 8q24 that harbors the focal-adhesion kinase (FAK) gene; the potential of this gene as a therapeutic target remains to be evaluated in OCCCs. We first examined the dependence of OCCCs on FAK and the PI3K/AKT signaling pathway. FAK was overexpressed in 20% of 67 OCCC samples, and this overexpression was correlated with its copy number gain. FAK copy number gains and mutations in PIK3CA accounted for about 40% of OCCC samples, suggesting that the FAK/PI3K/AKT axis is an attractive candidate for targeted therapeutics. We, therefore, treated ovarian cancer cell lines, including OCCC subtypes, with the FAK inhibitors PF-562,271 (PF271), and PF-573,228 (PF228). Ovarian cancer cells were more sensitive to PF271 than PF228. We then searched for single agents that exhibited a synergistic effect on cell death in combination with PF271. We found that co-treatment of PF271 with ABT-737, a BCL-2/BCL-XL antagonist, was profoundly effective at inducing apoptosis. RMGI and OVISE cells were more sensitive to ABT-737 than OVMANA and SKOV3 cells, which have PIK3CA mutations. Mechanistically, PF271 treatment resulted in the transient down-regulation of the anti-apoptotic protein MCL1 via the PI3K/AKT pathway. Therefore, PF271/ABT-737 treatment led to the inhibition of the anti-apoptotic proteins MCL1 and BCL-XL/BCL-2. We suggest that pharmacological inhibition of BCL-XL and FAK/PYK2 can be a potential therapeutic strategy for the treatment of OCCC.
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Authors | Heejei Yoon, Yoon-La Choi, Ji-Young Song, Ingu Do, So Young Kang, Young-Hyeh Ko, Sangyong Song, Byoung-Gie Kim |
Journal | PloS one
(PLoS One)
Vol. 9
Issue 2
Pg. e88587
( 2014)
ISSN: 1932-6203 [Electronic] United States |
PMID | 24523919
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- BCL2L1 protein, human
- MCL1 protein, human
- Myeloid Cell Leukemia Sequence 1 Protein
- bcl-X Protein
- Focal Adhesion Kinase 1
- Focal Adhesion Kinase 2
- PTK2 protein, human
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Topics |
- Adenocarcinoma, Clear Cell
(metabolism)
- Antineoplastic Agents
(pharmacology)
- Apoptosis
- Cell Line, Tumor
- Cell Proliferation
- Female
- Focal Adhesion Kinase 1
(antagonists & inhibitors)
- Focal Adhesion Kinase 2
(antagonists & inhibitors)
- Gene Dosage
- Humans
- Mutation
- Myeloid Cell Leukemia Sequence 1 Protein
(metabolism)
- Ovarian Neoplasms
(metabolism)
- Phosphorylation
- bcl-X Protein
(antagonists & inhibitors)
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