Nonamplified FGFR1 is a growth driver in malignant pleural mesothelioma

Our plain-English summary of Nonamplified FGFR1 is a growth driver in malignant pleural mesothelioma, by L.A. Marek, T.K. Hinz, A. von Mässenhausen, et al (Molecular Cancer Research, 2014).

The study

• Authors: L.A. Marek, T.K. Hinz, A. von Mässenhausen, K.A. Olszewski, E.K. Kleczko, D. Boehm, M.C. Weiser-Evans, R.A. Nemenoff, H. Hoffmann, A. Warth, J.M. Gozgit, S. Perner, L.E. Heasley
• Journal: Molecular Cancer Research
• Published: 2014;12(10):1460-9
• Cited by: 36 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Unlabelled: Malignant pleural mesothelioma (MPM) is associated with asbestos exposure and is a cancer that has not been significantly affected by small molecule-based targeted therapeutics. Previously, we demonstrated the existence of functional subsets of lung cancer and head and neck squamous cell carcinoma (HNSCC) cell lines in which fibroblast growth factor receptor (FGFR) autocrine signaling functions as a nonmutated growth pathway. In a panel of pleural mesothelioma cell lines, FGFR1 and FGF2 were coexpressed in three of seven cell lines and were significantly associated with sensitivity to the FGFR-active tyrosine kinase inhibitor (TKI), ponatinib, both in vitro and in vivo using orthotopically propagated xenografts. Furthermore, RNAi-mediated silencing confirmed the requirement for FGFR1 in specific mesothelioma cells and sensitivity to the FGF ligand trap, FP-1039, validated the requirement for autocrine FGFs. None of the FGFR1-dependent mesothelioma cells exhibited increased FGFR1 gene copy number, based on a FISH assay, indicating that increased FGFR1 transcript and protein expression were not mediated by gene amplification. Elevated FGFR1 mRNA was detected in a subset of primary MPM clinical specimens and like MPM cells; none harbored increased FGFR1 gene copy number. These results indicate that autocrine signaling through FGFR1 represents a targetable therapeutic pathway in MPM and that biomarkers distinct from increased FGFR1 gene copy number such as FGFR1 mRNA would be required to identify patients with MPM bearing tumors driven by FGFR1 activity.

Implications: FGFR1 is a viable therapeutic target in a subset of MPMs, but FGFR TKI-responsive tumors will need to be selected by a biomarker distinct from increased FGFR1 gene copy number, possibly FGFR1 mRNA or protein levels.

©2014 American Association for Cancer Research.

In plain English

This laboratory study of malignant pleural mesothelioma did not examine asbestos exposure. The authors studied a growth-signal receptor, FGFR1, in seven mesothelioma cell lines. Ponatinib, a drug that blocks FGFR1, slowed growth of the three lines with higher FGFR1 protein (H226, MSTO211H and H2452). FGFR1 protein levels were statistically significantly associated with ponatinib sensitivity (P = 0.023). Silencing FGFR1, or trapping its signal molecules with FP-1039, also slowed growth of FGFR1-expressing lines. None of the mesothelioma cell lines tested had extra copies of the FGFR1 gene. Among 168 archived pleural mesothelioma specimens from Heidelberg, Germany, 21 (12.5%) showed elevated FGFR1 mRNA, and none showed FGFR1 gene gain or amplification. In mice carrying H226 tumors in the chest, ponatinib shrank tumors in 3 of 5 mice after 6 weeks, but the treated tumors later grew again. The authors concluded that FGFR1 is a possible treatment target in a subset of mesotheliomas. They proposed that such tumors be identified by FGFR1 mRNA rather than by gene copy number.

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: experiments on mesothelioma cell lines, a mouse model with human tumor cells implanted in the chest, and analysis of archived human tumor specimens
• Who was studied: Seven pleural mesothelioma cell lines plus immortalized non-cancerous Met5A mesothelial cells; 168 surgically obtained pleural mesotheliomas treated 2002 to 2010 at the Thoraxklinik, Heidelberg University, Germany; published data on 53 primary tumors; immune-deficient mice in groups of 5
• Exposure: No asbestos exposure was studied. The experimental treatments were the drug ponatinib (20 mg/kg daily by mouth in mice), the FGF ligand trap FP-1039, and shRNAs that silence FGFR1.
• Main results:
  • Ponatinib caused dose-dependent growth inhibition of the H226, MSTO211H and H2452 mesothelioma cell lines. Table 1 gives IC50 values of 6, 7 and 50 nmol/L for these lines.
  • Across the cell lines, FGFR1 protein levels were statistically significantly associated with ponatinib IC50 values (Pearson r printed as 0.780; P = 0.023).
  • None of the mesothelioma cell lines assessed by FISH had an FGFR1 to chromosome 8 reference ratio above 2, meaning no FGFR1 gene amplification. The H1703 lung cancer cells used as a positive control had a ratio of 3.5.
  • The FGF ligand trap FP-1039 potently inhibited growth of H226 and H2452 cells and more modestly inhibited MSTO211H cells.
  • FGFR1-targeting shRNAs reduced FGFR1 mRNA and inhibited growth of H226 and MSTO211H cells.
  • Of the 168 archived pleural mesothelioma specimens, 21 (12.5%) had FGFR1 mRNA expression scored 2+.
  • None of the 168 archived tumors showed significant gains or amplification of the FGFR1 gene, whatever their FGFR1 mRNA level.
  • In published data on primary MPM tumors, 22 of 53 (42%) were positive for FGFR1 mRNA. Eight tumors (15% of total) expressed both FGFR1 and FGF2, and none showed increased FGFR1 gene copy number.
  • In mice with H226 tumors in the pleural space, ponatinib caused modest tumor shrinkage in 3 of 5 mice after 6 weeks, a statistically significant inhibition compared with control mice. Growth of the treated tumors increased after 8 weeks and eventually matched the control rate.
• The authors' conclusion: The authors concluded that FGFR1 signaling drives growth in a subset of mesothelioma cell lines and may be a treatment target. They proposed that FGFR1 mRNA levels in tumor specimens, rather than FGFR1 gene copy number, should serve as the marker of FGFR1 dependency in MPM.
• Limitations the authors state:
  • The assays were not sensitive enough to show clearly that ponatinib reduced FGFR1 phosphorylation in the cell lines.
  • The tumor response in mice was transient, likely because of acquired resistance.
  • The authors judged that FGFR inhibitors used alone are unlikely to cure FGFR1-dependent MPM.

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, Asbestos Exposure, Lung Cancer, Squamous Cell Carcinoma, Fibroblast, Tyrosine Kinase Inhibitor, Mesothelioma, Fluorescence In Situ Hybridization (FISH).

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