Analyses of merlin/NF2 connection to FAK inhibitor responsiveness in serous ovarian cancer.

Autor: Shah NR; Department of Reproductive Medicine, UCSD Moores Cancer Center, La Jolla, CA 92093, United States., Tancioni I; Department of Reproductive Medicine, UCSD Moores Cancer Center, La Jolla, CA 92093, United States., Ward KK; Department of Reproductive Medicine, UCSD Moores Cancer Center, La Jolla, CA 92093, United States., Lawson C; Department of Reproductive Medicine, UCSD Moores Cancer Center, La Jolla, CA 92093, United States., Chen XL; Department of Reproductive Medicine, UCSD Moores Cancer Center, La Jolla, CA 92093, United States., Jean C; Department of Reproductive Medicine, UCSD Moores Cancer Center, La Jolla, CA 92093, United States., Sulzmaier FJ; Department of Reproductive Medicine, UCSD Moores Cancer Center, La Jolla, CA 92093, United States., Uryu S; Department of Reproductive Medicine, UCSD Moores Cancer Center, La Jolla, CA 92093, United States., Miller NL; Department of Reproductive Medicine, UCSD Moores Cancer Center, La Jolla, CA 92093, United States., Connolly DC; Developmental Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United States., Schlaepfer DD; Department of Reproductive Medicine, UCSD Moores Cancer Center, La Jolla, CA 92093, United States. Electronic address: dschlaepfer@ucsd.edu.
Jazyk: angličtina
Zdroj: Gynecologic oncology [Gynecol Oncol] 2014 Jul; Vol. 134 (1), pp. 104-11. Date of Electronic Publication: 2014 Apr 27.
DOI: 10.1016/j.ygyno.2014.04.044
Abstrakt: Objective: Focal adhesion kinase (FAK) is overexpressed in serous ovarian cancer. Loss of merlin, a product of the neurofibromatosis 2 tumor suppressor gene, is being evaluated as a biomarker for FAK inhibitor sensitivity in mesothelioma. Connections between merlin and FAK in ovarian cancer remain undefined.
Methods: Nine human and two murine ovarian cancer cell lines were analyzed for growth in the presence of a small molecule FAK inhibitor (PF-271, also termed VS-6062) from 0.1 to 1 μM for 72 h. Merlin was evaluated by immunoblotting and immunostaining of a human ovarian tumor tissue array. Growth of cells was analyzed in an orthotopic tumor model and evaluated in vitro after stable shRNA-mediated merlin knockdown.
Results: Greater than 50% inhibition of OVCAR8, HEY, and ID8-IP ovarian carcinoma cell growth occurred with 0.1 μM PF-271 in anchorage-independent (p<0.001) but not in adherent culture conditions. PF-271-mediated reduction in FAK Y397 phosphorylation occurred independently of growth inhibition. Suspended growth of OVCAR3, OVCAR10, IGROV1, IGROV1-IP, SKOV3, SKOV3-IP, A2780, and 5009-MOVCAR was not affected by 0.1 μM PF-271. Merlin expression did not correlate with serous ovarian tumor grade or stage. PF-271 (30 mg/kg, BID) did not inhibit 5009-MOVCAR tumor growth and merlin knockdown in SKOV3-IP and OVCAR10 cells did not alter suspended cell growth upon PF-271 addition.
Conclusions: Differential responsiveness to FAK inhibitor treatment was observed. Intrinsic low merlin protein level correlated with PF-271-mediated anchorage-independent growth inhibition, but reduction in merlin expression did not induce sensitivity to FAK inhibition. Merlin levels may be useful for patient stratification in FAK inhibitor trials.
(Copyright © 2014 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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