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Targeted inhibition of FAK, PYK2 and BCL-XL synergistically enhances apoptosis in ovarian clear cell carcinoma cell lines.

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.
AuthorsHeejei Yoon, Yoon-La Choi, Ji-Young Song, Ingu Do, So Young Kang, Young-Hyeh Ko, Sangyong Song, Byoung-Gie Kim
JournalPloS one (PLoS One) Vol. 9 Issue 2 Pg. e88587 ( 2014) ISSN: 1932-6203 [Electronic] United States
PMID24523919 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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
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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