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

• Published in: PloS one 2014-02, Vol.9 (2), p.e88587-e88587
• Main Authors: Yoon, Heejei, Choi, Yoon-La, Song, Ji-Young, Do, Ingu, Kang, So Young, Ko, Young-Hyeh, Song, Sangyong, Kim, Byoung-Gie
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Adenocarcinoma, Clear Cell - metabolism; AKT protein; Antineoplastic Agents - pharmacology; Apoptosis; Bcl-2 protein; Bcl-x protein; bcl-X Protein - antagonists & inhibitors; Biology; Biotechnology; Cancer; Carcinoma; Cell adhesion & migration; Cell death; Cell Line, Tumor; Cell Proliferation; Chemotherapy; Copy number; Drug development; Female; Focal adhesion kinase; Focal Adhesion Kinase 1 - antagonists & inhibitors; Focal Adhesion Kinase 2 - antagonists & inhibitors; Gene Dosage; Health aspects; Humans; Inhibition; Kinases; Mcl-1 protein; Medicine; Mutation; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Ovarian cancer; Ovarian carcinoma; Ovarian Neoplasms - metabolism; Pharmacology; Phosphorylation; Proteins; Signal transduction; Signaling; Synergistic effect; Tumor cell lines
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0088587

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.