Fibroblast growth factor receptor inhibition is active against mesothelioma and synergizes with radio- and chemotherapy

Our plain-English summary of Fibroblast growth factor receptor inhibition is active against mesothelioma and synergizes with radio- and chemotherapy, by K. Schelch, M.A. Hoda, T. Klikovits, et al (American Journal of Respiratory and Critical Care Medicine, 2014).

The study

• Authors: K. Schelch, M.A. Hoda, T. Klikovits, J. Münzker, B. Ghanim, C. Wagner, T. Garay, V. Laszlo, U. Setinek, B. Dome, M. Filipits, C. Pirker, P. Heffeter, E. Selzer, J. Tovari, S. Torok, I. Kenessey, K. Holzmann, B. Grasl-Kraupp, B. Marian, W. Klepetko, W. Berger, B. Hegedus, M. Grusch
• Journal: American Journal of Respiratory and Critical Care Medicine
• Published: 2014;190(7):763-72
• Cited by: 54 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Rationale: Malignant pleural mesothelioma is an aggressive malignancy characterized by frequent resistance to chemo- and radiotherapy, poor outcome, and limited therapeutic options. Fibroblast growth factors (FGFs) and their receptors are potential targets for cancer therapy, but their significance in mesothelioma has remained largely undefined.

Objectives: To investigate the antimesothelioma potential of FGF receptor 1 (FGFR1) inhibition.

Methods: Expression of FGFs and their receptors was analyzed in mesothelioma cell lines and tissue specimens. Several cell models were used to investigate FGFR1 inhibition in vitro and in combination with cisplatin and irradiation. Mouse intraperitoneal xenotransplant models were used for in vivo validation.

Measurements And Main Results: FGFR1, FGF2, and FGF18 were overexpressed in mesothelioma. Stimulation with FGF2 led to increased cell proliferation, migration, and transition to a more sarcomatoid phenotype in subsets of mesothelioma cell lines. In contrast, inhibition of FGFR1 by a specific kinase inhibitor or a dominant-negative FGFR1 construct led to significantly decreased proliferation, clonogenicity, migration, spheroid formation, and G1 cell cycle arrest in several mesothelioma cell lines, accompanied by apoptosis induction and decreased mitogen-activated protein kinase pathway activity. Reduced tumor growth, proliferation, mitogenic signaling, and apoptosis induction were observed in vivo. Inhibition of FGFR1 synergistically enhanced the cytotoxic effects of ionizing radiation and cisplatin.

Conclusions: Our data suggest that the malignant phenotype of mesothelioma cells depends on intact FGF signals, which should be considered as therapeutic targets with a promising chemo- and radiosensitizing potential.

In plain English

This laboratory study examined fibroblast growth factor (FGF) signaling in malignant pleural mesothelioma. It did not study asbestos exposure. The authors measured FGFs and their receptors in cell lines and in tumor tissue from 69 patients. They blocked one receptor, FGFR1, with a drug (PD166866) or a genetic construct, in cells and in mice carrying human mesothelioma cells. Of the 44 tumor specimens that could be evaluated for FGFR1, staining was moderate in 48% and strong in 45%. A single normal pleura control showed no staining in its mesothelial layer. Blocking FGFR1 strongly impaired growth of mesothelioma cell lines, and the non-cancerous mesothelial cells tested resisted the drug. In mice, both approaches strongly reduced tumor burden from P31 cells. With SPC111 cells carrying the genetic construct, the reduction was minor and not statistically significant. The drug combined with cisplatin had additive or synergistic effects at most doses in three cell lines. It did not restore sensitivity in a cisplatin-resistant line. In cultured cells, blocking FGFR1 also increased radiation sensitivity. The authors concluded the findings warrant further evaluation of FGFR-targeting strategies as potential mesothelioma therapies.

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 using human mesothelioma cell lines, human tumor tissue specimens (immunohistochemistry), and mouse intraperitoneal xenograft experiments
• Who was studied: Tumor tissue from 69 patients with malignant pleural mesothelioma (48 epithelioid, 18 biphasic, 3 sarcomatoid) who had surgery between 1993 and 2013. Of these, 44, 69 and 64 specimens could be evaluated for FGFR1, FGF2 and FGF18 respectively. Normal pleura from one pneumothorax patient served as the control. The study also used mesothelioma cell lines (12 in microarray data, 9 by PCR, 6 in functional tests), non-cancerous mesothelial cell cultures, and SCID mice.
• Exposure: No asbestos exposure was studied. The experimental treatments blocked FGFR1, either with the inhibitor drug PD166866 or with a dominant-negative FGFR1 adenovirus construct (Ad-dnFGFR1). These were given alone or combined with cisplatin or 2 Gy irradiation. Cells were also stimulated with FGF2.
• Main results:
  • Among the evaluable mesothelioma tissue specimens (44 for FGFR1, 69 for FGF2, 64 for FGF18), the shares with no, weak, moderate and strong staining were as follows: FGFR1, 0, 7, 48 and 45%; FGF2, 10, 17, 42 and 31%; FGF18, 42, 30, 25 and 3%.
  • In the normal pleura control from one pneumothorax patient, none of the three proteins was detected in the mesothelial layer.
  • The FGFR1 inhibitor strongly impaired proliferation and colony formation of mesothelioma cell lines.
  • The non-cancerous mesothelial cells tested were resistant to PD166866.
  • Mice injected with P31 cells carrying the dominant-negative FGFR1 construct showed a strong reduction in total tumor burden.
  • With SPC111 cells carrying the dominant-negative FGFR1 construct, tumor weight fell only slightly, and the reduction was not statistically significant.
  • In P31-bearing mice treated with PD166866, tumor burden was greatly reduced.
  • In cell viability assays, PD166866 combined with cisplatin had additive or synergistic effects for most doses tested in SPC111, SPC212 and P31 cells.
  • In the cisplatin-resistant line P31res1.2, FGFR1 inhibition did not restore sensitivity to cisplatin.
  • In cultured mesothelioma cell lines, blocking FGFR signals 24 hours after 2 Gy irradiation increased the cells' sensitivity to radiation. This combination was tested in cell viability assays, not in mice or patients.
  • In the patient tissue, FGF2 expression was not correlated with disease outcome.
• The authors' conclusion: The authors concluded that inhibiting FGFR1 impaired mesothelioma cell growth and migration and potentiated chemo- or radiotherapy. In their view, this warrants further evaluation of FGFR-targeting strategies as potential antimesothelioma therapies.
• Limitations the authors state:
  • The association of FGFR1 expression with late-stage disease was based on a relatively small sample of 44 specimens.
  • FGFR1 protein levels may not reflect signaling activity. In the cell lines, FGFR1 protein level did not correlate with sensitivity to PD166866.

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: Fibroblast, Mesothelioma, Chemotherapy, Pleural Mesothelioma, Cisplatin, Sarcomatoid, Apoptosis.

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