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

Our plain-English summary of Analyses of merlin/NF2 connection to FAK inhibitor responsiveness in serous ovarian cancer, by N.R. Shah, I. Tancioni, K.K. Ward, et al (Gynecologic Oncology, 2014).

The study

• Authors: N.R. Shah, I. Tancioni, K.K. Ward, C. Lawson, X.L. Chen, C. Jean, F.J. Sulzmaier, S. Uryu, N.L. Miller, D.C. Connolly, D.D. Schlaepfer
• Journal: Gynecologic Oncology
• Published: 2014;134(1):104-11
• Cited by: 49 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This laboratory study did not examine asbestos. It concerned ovarian cancer. The authors tested whether PF-271, a drug that blocks focal adhesion kinase (FAK), slowed growth of nine human and two mouse ovarian cancer cell lines over 72 hours. They also asked whether levels of merlin, a protein made by the NF2 gene, matched the response. Merlin was of interest because a trial in malignant pleural mesothelioma is testing it as a marker. In suspended culture, HEY, OVCAR8 and mouse ID8-IP cells were strongly inhibited at 0.1 μM, but eight other lines were not. Grown attached to plastic, HEY and OVCAR8 were not inhibited. Merlin was highest in insensitive lines and lowest in sensitive ones. In tissue from 48 serous ovarian cancers, merlin did not correlate with tumor grade or stage. In mice with high-merlin 5009-MOVCAR tumors, the drug did not significantly change tumor weight, though metastases were fewer. Reducing merlin in two resistant lines did not make them sensitive. The authors concluded that merlin level may predict response but found no direct causal link.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: drug testing on cancer cell lines, staining of a human tumor tissue array, and an experiment in mice with tumors grown on the ovary (orthotopic tumor model)
• Who was studied: Nine human and two mouse ovarian cancer cell lines; a tissue array of 58 patient samples (48 serous ovarian cancer, 10 normal or adjacent ovarian tissue); mice implanted with 5009-MOVCAR tumors (11 vehicle-treated, 12 PF-271-treated)
• Exposure: No asbestos exposure was studied. The exposure was the FAK inhibitor drug PF-271: 0.1 to 1 μM for 72 hours in cell culture, and 30 mg/kg by mouth twice daily from Day 7 to Day 28 in mice. Merlin levels were also reduced in some cells using shRNA.
• Main results:
  • In suspended (anchorage-independent) culture, HEY and OVCAR8 cell numbers fell sharply at 0.1 μM PF-271 after 72 hours
  • SKOV3, SKOV3-IP, IGROV1-IP and OVCAR10 cells showed no significant growth inhibition even at 1 μM PF-271
  • When grown attached to plastic, HEY and OVCAR8 cells were not growth-inhibited by 0.1 μM PF-271
  • PF-271 reduced FAK Y397 phosphorylation (a marker of FAK activity), but this reduction did not predict growth inhibition
  • Among the cell lines, merlin was highest in insensitive cells and lowest in sensitive cells
  • In the human tumor tissue array, merlin staining did not correlate with serous ovarian tumor grade or stage
  • In mice with 5009-MOVCAR tumors, primary tumor weight did not differ significantly between PF-271-treated and vehicle-treated mice
  • PF-271-treated mice showed less metastatic spread
  • Reducing merlin in SKOV3-IP and OVCAR10 cells did not change their growth in the presence of PF-271
• The authors' conclusion: The authors concluded that tumor merlin level may predict responsiveness to FAK inhibition, though they found no direct causal link between FAK and merlin. They suggested that merlin level may be considered for grouping patients in future ovarian cancer trials of FAK inhibitors.
• Limitations the authors state:
  • The authors stated that the mechanistic link, if any, between merlin and FAK still needs investigation

Topics

The National Library of Medicine indexes this study under subjects our site covers: Ovarian cancer.

Medical terms in this study, explained in our Lexicon: Merlin, Ovarian Cancer, Tumor Suppressor Gene, Biomarker, Mesothelioma, Carcinoma.

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• E-cadherin expression is correlated with focal adhesion kinase inhibitor resistance in Merlin-negative malignant mesothelioma cells — T. Kato, T. Sato, et al. (2017)
• The Role of E-Cadherin and microRNA on FAK Inhibitor Response in Malignant Pleural Mesothelioma (MPM) — M.L. Yuen, L. Zhuang, et al. (2021)
• PAX8 reliably distinguishes ovarian serous tumors from malignant mesothelioma — A.R. Laury, J.L. Hornick, et al. (2010)
• Expression of the Ets transcription factor EHF in serous ovarian carcinoma effusions is a marker of poor survival — K. Brenne, D.A. Nymoen, et al. (2012)
• The p53/mouse double minute 2 homolog complex deregulation in merlin-deficient tumours — S. Ammoun, M.C. Schmid, et al. (2015)

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