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

PLoS One. 2014 Feb 11;9(2):e88587. doi: 10.1371/journal.pone.0088587. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • 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

Grants and funding

This study was supported by grants from the Korea Healthcare Technology R&D Project, Ministry for Health & Welfare Affairs, Republic of Korea (A092255), the Samsung Biomedical Research Institute grants (#SBRI SP1-B2-021-2 and #SBRI SP1-B2-022-2) and the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A0920010). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.