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

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

  • J Mol Med (Berl). 2019 Feb;97(2):231-242. doi: 10.1007/s00109-018-1725-7.
Viktoria Laszlo 1 2,  Zsuzsanna Valko 1 3,  Judit Ozsvar 1,  Ildiko Kovacs 3,  Tamas Garay 4,  Mir Alireza Hoda 1,  Thomas Klikovits 1,  Paul Stockhammer 1 5,  Clemens Aigner 5,  Marion Gröger 6,  Walter Klepetko 1,  Walter Berger 7,  Michael Grusch 7,  Jozsef Tovari 8 9,  Irene C Waizenegger 10,  Balazs Dome 11 12 13,  Balazs Hegedus 14 15 16
Affiliations

Affiliations

  • 1 Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria.
  • 2 Department of Biomedical Imaging and Image-guided Therapy, Division of Molecular and Gender Imaging, Medical University of Vienna, Vienna, Austria.
  • 3 Department of Tumor Biology, National Korányi Institute of Pulmonology, Budapest, Hungary.
  • 4 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
  • 5 Department of Thoracic Surgery, Ruhrlandklinik, University Clinic Essen, University Duisburg-Essen, Tüschener Weg 40, 45239, Essen, Germany.
  • 6 Core Facility Imaging, Medical University of Vienna, Vienna, Austria.
  • 7 Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
  • 8 Department of Experimental Pharmacology, National Institute of Oncology, Budapest, Hungary.
  • 9 KINETO Lab Ltd, Budapest, Hungary.
  • 10 Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
  • 11 Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria. balazs.dome@meduniwien.ac.at.
  • 12 Department of Tumor Biology, National Korányi Institute of Pulmonology, Budapest, Hungary. balazs.dome@meduniwien.ac.at.
  • 13 Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, Budapest, Hungary. balazs.dome@meduniwien.ac.at.
  • 14 Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria. balazs.hegedues@rlk.uk-essen.de.
  • 15 2nd Department of Pathology, Semmelweis University, Budapest, Hungary. balazs.hegedues@rlk.uk-essen.de.
  • 16 Department of Thoracic Surgery, Ruhrlandklinik, University Clinic Essen, University Duisburg-Essen, Tüschener Weg 40, 45239, Essen, Germany. balazs.hegedues@rlk.uk-essen.de.
PMID: 30539198 DOI: 10.1007/s00109-018-1725-7
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. IC50 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, IC50 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.

Keywords

Angiogenesis; Focal adhesion kinase; Mesothelioma; Orthotopic xenograft; Spheroid formation; Tyrosine kinase inhibitor.

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