title: 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.
authors: Institute for Refractory Cancer Research, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Heejei
authors: H
authors: Yoon
authors: Institute for Refractory Cancer Research, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea ; Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Yoon-La
authors: YL
authors: Choi
authors: Institute for Refractory Cancer Research, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Ji-Young
authors: JY
authors: Song
authors: Samsung Cancer Research Institute. Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Ingu
authors: I
authors: Do
authors: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: So Young
authors: SY
authors: Kang
authors: Institute for Refractory Cancer Research, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea ; Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea ; Samsung Cancer Research Institute. Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Young-Hyeh
authors: YH
authors: Ko
authors: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Sangyong
authors: S
authors: Song
authors: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Byoung-Gie
authors: BG
authors: Kim
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors*; D051418:Focal Adhesion Kinase 2 / Q000037:antagonists & inhibitors*; D018628:Gene Dosage; D006801:Humans; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D051020:bcl-X Protein; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; C496050:PTK2 protein, human