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

Our plain-English summary of The FAK inhibitor BI 853520 inhibits spheroid formation and orthotopic tumor growth in malignant pleural mesothelioma, by V. Laszlo, Z. Valko, J. Ozsvar, et al (Journal of Molecular Medicine, 2019).

The study

• Authors: V. Laszlo, Z. Valko, J. Ozsvar, I. Kovacs, T. Garay, M.A. Hoda, T. Klikovits, P. Stockhammer, C. Aigner, M. Gröger, W. Klepetko, W. Berger, M. Grusch, J. Tovari, I.C. Waizenegger, B. Dome, B. Hegedus
• Journal: Journal of Molecular Medicine
• Published: 2019;97(2):231-242
• Cited by: 38 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This lab and animal study did not examine asbestos exposure. The authors tested BI 853520, an experimental focal adhesion kinase (FAK) blocker, on 12 human malignant pleural mesothelioma cell lines and in mice. In flat (adherent) cultures the drug had limited effect: all lines needed over 5 μM to halve viability, three over 10 μM. Sensitivity was not associated with tumor subtype or merlin status. With cisplatin, tested in two flat-grown cell lines, effects were mostly additive or antagonistic, not synergistic. At 1 μM the drug reduced cell movement in three of four lines; P31 cells moved slightly more. It cut spheroid (tumor-cell cluster) numbers; P31 cells formed none at 0.1 or 1 μM. In female SCID mice with P31 chest tumors, 3 weeks of oral 20 mg/kg treatment significantly lowered tumor weight (P = 0.0183), proliferation (P = 0.0012) and blood-vessel density (P = 0.0159). The authors saw no increase in apoptosis (programmed cell death) on TUNEL staining of the treated tumors. The authors concluded the drug has limited activity in flat cultures but inhibits spheroid and mouse tumor growth.

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: Preclinical laboratory study (cell culture experiments) plus an animal experiment in mice with tumors grown in the chest cavity (orthotopic xenograft)
• Who was studied: 12 human malignant pleural mesothelioma cell lines (epithelioid, biphasic and sarcomatoid), obtained from Zurich, Helsinki and Umea or established at the Medical University of Vienna, plus one non-malignant immortalized mesothelial cell line (Met5a). Also 8-week-old female SCID (immunocompromised) mice implanted in the chest with P31 mesothelioma cells. The number of mice is not stated.
• Exposure: No asbestos exposure was studied. The exposure was the FAK inhibitor drug BI 853520: various concentrations in cell cultures (for example 0.1 and 1 μM in spheroid assays, 1 μM in migration tests), alone or with cisplatin; in mice, 20 mg/kg by mouth five days a week for 3 weeks, compared with solvent.
• Main results:
  • In adherent cultures, all 12 MPM cell lines had IC50 values above 5 μM; three cell lines had very low sensitivity (IC50 above 10 μM).
  • Sensitivity to the drug in these cell lines showed no association with histological subtype or merlin expression.
  • Combined with cisplatin in two cell lines (P31 and SPC212) grown as adherent cultures, the interaction was only additive or antagonistic at most concentrations; no synergism was detected.
  • At 1 μM, the drug reduced migration of SPC111, SPC212 and M38K cells; P31 cells showed a slight increase in migration.
  • The drug reduced FAK activation (phosphorylation) in the four cell lines studied, but did not produce a sustained reduction in activation of the downstream signals Akt, S6 or Erk.
  • Spheroid numbers fell significantly, depending on cell line, at concentrations below those affecting adherent growth; P31 cells formed no spheroids at 0.1 or 1 μM. Spheroid diameter did not change significantly.
  • Treatment of spheroids did not change expression of the putative tumor stem cell markers tested.
  • In mice, treated animals had significantly lower tumor loads than solvent-treated controls (P = 0.0183).
  • In mice, treatment did not influence weight loss.
  • Tumor-cell proliferation (Ki67 labeling) was significantly reduced in treated mice (P = 0.0012).
  • Increased apoptosis, as detected by TUNEL labeling, was not observed in the treated mouse tumors.
  • Microvessel density in tumors was significantly reduced in the 20 mg/kg treated group (P = 0.0159).
• The authors' conclusion: The authors concluded that BI 853520 has only limited activity in adherent 2D cell cultures but effectively inhibits 3D tumor spheroid growth and blocked the growth of orthotopically growing human MPM xenografts in mice, and that additional studies are needed.
• Limitations the authors state:
  • None of the cell lines expressed E-cadherin, so its effect on treatment response could not be studied.
  • Only four NF2 (merlin)-expressing cell lines were included.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Tyrosine Kinase Inhibitor, STEM, Apoptosis, Cisplatin.

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