Expression of FGFR1-4 in Malignant Pleural Mesothelioma Tissue and Corresponding Cell Lines and its Relationship to Patient Survival and FGFR Inhibitor Sensitivity

Our plain-English summary of Expression of FGFR1-4 in Malignant Pleural Mesothelioma Tissue and Corresponding Cell Lines and its Relationship to Patient Survival and FGFR Inhibitor Sensitivity, by G. Vlacic, M.A. Hoda, T. Klikovits, et al (Cells, 2019).

The study

• Authors: G. Vlacic, M.A. Hoda, T. Klikovits, K. Sinn, E. Gschwandtner, K. Mohorcic, K. Schelch, C. Pirker, B. Peter-Vörösmarty, J. Brankovic, B. Dome, V. Laszlo, T. Cufer, A. Rozman, W. Klepetko, B. Grasl-Kraupp, B. Hegedus, W. Berger, I. Kern, M. Grusch
• Journal: Cells
• Published: 2019;8(9)
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a devastating malignancy with limited therapeutic options. Fibroblast growth factor receptors (FGFR) and their ligands were shown to contribute to MPM aggressiveness and it was suggested that subgroups of MPM patients could benefit from FGFR-targeted inhibitors. In the current investigation, we determined the expression of all four FGFRs (FGFR1-FGFR4) by immunohistochemistry in tissue samples from 94 MPM patients. From 13 of these patients, we were able to establish stable cell lines, which were subjected to FGFR1-4 staining, transcript analysis by quantitative RT-PCR, and treatment with the FGFR inhibitor infigratinib. While FGFR1 and FGFR2 were widely expressed in MPM tissue and cell lines, FGFR3 and FGFR4 showed more restricted expression. FGFR1 and FGFR2 showed no correlation with clinicopathologic data or patient survival, but presence of FGFR3 in 42% and of FGFR4 in 7% of patients correlated with shorter overall survival. Immunostaining in cell lines was more homogenous than in the corresponding tissue samples. Neither transcript nor protein expression of FGFR1-4 correlated with response to infigratinib treatment in MPM cell lines. We conclude that FGFR3 and FGFR4, but not FGFR1 or FGFR2, have prognostic significance in MPM and that FGFR expression is not sufficient to predict FGFR inhibitor response in MPM cell lines.

In plain English

This laboratory and clinical study measured four related proteins, the fibroblast growth factor receptors FGFR1 to FGFR4, in malignant pleural mesothelioma. The study did not examine asbestos exposure. The authors stained tumor tissue from 94 patients treated in Vienna, Austria, or Golnik, Slovenia, between 2006 and 2015. Full follow-up was available for 81 of them. FGFR1 and FGFR2 were strongly and widely present, while FGFR3 and FGFR4 were weaker and less common. FGFR1 staining was not significantly linked to survival, and FGFR2 was strong in all patients. The 47 patients without FGFR3 staining had significantly longer overall survival (P = 0.043). FGFR4, found in 6 of 81 patients (7.4%), was linked to shorter survival (P = 0.0027). Cell lines grown from 13 patients stained more uniformly than their original tumors. When the lines were treated with the drug infigratinib, 3 were sensitive, 6 intermediate and 4 resistant. Neither receptor protein nor receptor mRNA levels matched this response. The authors concluded that FGFR3 and FGFR4 have prognostic value in this disease, but FGFR expression did not satisfactorily predict which cell lines would respond to the drug.

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: Retrospective study of patient tumor tissue (immunohistochemistry staining and survival analysis), combined with laboratory experiments on cell lines grown from patients' tumors
• Who was studied: Tumor tissue from 94 malignant pleural mesothelioma patients referred between 2006 and 2015 to the Medical University of Vienna, Austria, or the University Clinic Golnik, Slovenia. Full follow-up was available for 81 patients (41 Austria, 40 Slovenia). Stable cell lines were established from 13 patients.
• Exposure: No asbestos exposure was studied. The study measured expression of FGFR1 to FGFR4 (protein by staining, mRNA by qRT-PCR). Cell lines were treated with the FGFR1-3 inhibitor infigratinib or the FGFR4-specific inhibitor BLU9931 at 0.1 to 10 µM.
• Main results:
  • In the 94 tumor tissues, FGFR1 and FGFR2 stained strongly; FGFR3 and FGFR4 showed weaker and more restricted expression.
  • All patients with follow-up data had strong FGFR2 staining, so FGFR2 was not compared with clinical data.
  • FGFR1 staining intensity was not significantly correlated with patient survival.
  • Among the 81 patients with follow-up, the 47 without FGFR3 staining had significantly longer overall survival than the 34 with staining (P = 0.043).
  • FGFR4 was detectable in 6 of 81 patients (7.4%) and was correlated with shorter overall survival (P = 0.0027).
  • FGFR4 staining was found in 4 of 22 female patients and 2 of 59 male patients.
  • Of the 13 patient-derived cell lines treated with infigratinib, 3 were classified as sensitive (IC50 below 0.5 µM), 4 as resistant (IC50 above 10 µM or no inhibition), and 6 as intermediate.
  • Infigratinib sensitivity of the cell lines did not correlate with the FGFR1 or FGFR3 staining scores of the tumors they came from.
  • The 13 cell lines stained more uniformly than their tumors: all had strong FGFR1 and FGFR2, weak FGFR3, and no detectable FGFR4.
  • In the cell lines, FGFR1 mRNA level did not correlate with infigratinib sensitivity (R2 = 0.041, P = 0.5485).
  • The link between FGFR4 mRNA and BLU9931 sensitivity was not statistically significant. The two cell lines with the highest FGFR4 mRNA were the most sensitive to BLU9931.
• The authors' conclusion: The authors concluded that FGFR3 and FGFR4 have prognostic value in MPM, while FGFR1 and FGFR2 are often co-expressed but do not correlate with survival or clinicopathologic features. They also reported that FGFR1-4 expression did not satisfactorily predict which cell lines were sensitive to FGFR inhibition.
• Limitations the authors state:
  • Because there were few biphasic (13) and sarcomatoid (7) tumors, these were combined as non-epithelioid for analysis.
  • Larger patient groups are needed to clarify the prognostic value of FGFR expression in the different histological subtypes.
  • Strong FGFR2 staining did not match low FGFR2 mRNA in the cell lines. The authors suggest antibody cross-reactivity or splice variants not detected by the probe.
  • Cell culture conditions may have favored particular expression patterns, which could explain why the cell lines were more uniform than the tumors.

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, Fibroblast, Immunohistochemistry, Overall Survival.

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