The FAK inhibitor BI 853520 inhibits spheroid formation and orthotopic tumor growth in malignant pleural mesothelioma

Viktoria Laszlo, Zsuzsanna Valko, Judit Ozsvar, Ildiko Kovacs, Tamas Garay, Mir Alireza Hoda, Thomas Klikovits, Paul Stockhammer, Clemens Aigner, Marion Gröger, Walter Klepetko, Walter Berger, Michael Grusch, Jozsef Tovari, Irene C. Waizenegger, Balazs Dome, Balazs Hegedus

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Abstract: No tyrosine kinase inhibitors are approved for malignant pleural mesothelioma (MPM). Preclinical studies identified focal adhesion kinase (FAK) as a target in MPM. Accordingly, we assessed the novel, highly selective FAK inhibitor (BI 853520) in 2D and 3D cultures and in vivo. IC 50 values were measured by adherent cell viability assay. Cell migration and 3D growth were quantified by video microscopy and spheroid formation, respectively. Phosphorylation of FAK, Akt, S6, and Erk was measured by immunoblot. The mRNA expression of the putative tumor stem cell markers SOX2, Nanog, CD44, ALDH1, c-myc, and Oct4 was analyzed by qPCR. Cell proliferation, apoptosis, and tumor tissue microvessel density (MVD) were investigated in orthotopic MPM xenografts. In all 12 MPM cell lines, IC 50 exceeded 5 μM and loss of NF2 did not correlate with sensitivity. No synergism was found with cisplatin in adherent cells. BI 853520 decreased migration in 3 out of 4 cell lines. FAK phosphorylation was reduced upon treatment but activation of Erk, Akt, or S6 remained unaffected. Nevertheless, BI 853520 inhibited spheroid growth and significantly reduced tumor weight, cell proliferation, and MVD in vivo. BI 853520 has limited effect in adherent cultures but demonstrates potent activity in spheroids and in orthotopic tumors in vivo. Based on our findings, further studies are warranted to explore the clinical utility of BI 853520 in human MPM. Key messages: Response to FAK inhibition in MPM is independent of NF2 expression or histotype.FAK inhibition strongly interfered with MPM spheroid formation.BI 853520 has been shown to exert anti-tumor effect in MPM.

Original languageEnglish
Pages (from-to)231-242
Number of pages12
JournalJournal of Molecular Medicine
Volume97
Issue number2
DOIs
Publication statusPublished - Feb 7 2019

Keywords

  • Angiogenesis
  • Focal adhesion kinase
  • Mesothelioma
  • Orthotopic xenograft
  • Spheroid formation
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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  • Cite this

    Laszlo, V., Valko, Z., Ozsvar, J., Kovacs, I., Garay, T., Hoda, M. A., Klikovits, T., Stockhammer, P., Aigner, C., Gröger, M., Klepetko, W., Berger, W., Grusch, M., Tovari, J., Waizenegger, I. C., Dome, B., & Hegedus, B. (2019). The FAK inhibitor BI 853520 inhibits spheroid formation and orthotopic tumor growth in malignant pleural mesothelioma. Journal of Molecular Medicine, 97(2), 231-242. https://doi.org/10.1007/s00109-018-1725-7