Combined Inhibition of EZH2 and FGFR is Synergistic in BAP1-deficient Malignant Mesothelioma

Our plain-English summary of Combined Inhibition of EZH2 and FGFR is Synergistic in BAP1-deficient Malignant Mesothelioma, by J. Badhai, N. Landman, G.K. Pandey, et al (Cancer Research Communications, 2024).

The study

• Authors: J. Badhai, N. Landman, G.K. Pandey, J.Y. Song, D. Hulsman, O. Krijgsman, G. Chandrasekaran, A. Berns, M. van Lohuizen
• Journal: Cancer Research Communications
• Published: 2024;4(1):18-27
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Unlabelled: Malignant mesothelioma is a highly aggressive tumor with a survival of only 4-18 months after diagnosis. Treatment options for this disease are limited. Immune checkpoint blockade using ipilimumab and nivolumab has recently been approved as a frontline therapy, but this led to only a small improvement in overall patient survival. As more than half of patients with mesothelioma have alterations in the gene encoding for BAP1 this could be a potential marker for targeted therapies. In this study, we investigated the synergistic potential of combining EZH2 inhibition together with FGFR inhibition for treatment of BAP1-deficient malignancies. The efficacy of the combination was evaluated using human and murine preclinical models of mesothelioma and uveal melanoma in vitro. The efficacy of the combination was further validated in vivo by using BAP1-deficient mesothelioma xenografts and autochthonous mouse models. In vitro data showed sensitivity to the combined inhibition in BAP1-deficient mesothelioma and uveal melanoma tumor cell lines but not for BAP1-proficient subtypes. In vivo data showed susceptibility to the combination of BAP1-deficient xenografts and demonstrated an increase of survival in autochthonous models of mesothelioma. These results highlight the potential of this novel drug combination for the treatment of mesothelioma using BAP1 as a biomarker. Given these encouraging preclinical results, it will be important to clinically explore dual EZH2/FGFR inhibition in patients with BAP1-deficient malignant mesothelioma and justify further exploration in other BAP1 loss-associated tumors.

Significance: Despite the recent approval of immunotherapy, malignant mesothelioma has limited treatment options and poor prognosis. Here, we observe that EZH2 inhibitors dramatically enhance the efficacy of FGFR inhibition, sensitising BAP1-mutant mesothelioma and uveal melanoma cells. The striking synergy of EZH2 and FGFR inhibition supports clinical investigations for BAP1-mutant tumors.

© 2024 The Authors; Published by the American Association for Cancer Research.

In plain English

This was a laboratory study using cells and mice. It did not study asbestos exposure or human patients. The authors tested whether combining two kinds of drugs worked against malignant mesothelioma that lacks a working BAP1 gene. The drugs were EZH2 inhibitors (GSK126 or tazemetostat) and an FGFR inhibitor (AZD4547). In mouse and human mesothelioma cell lines, the combination showed strong synergy and an almost complete loss of cell survival, but only in BAP1-deficient lines. Uveal melanoma cell lines showed the same pattern. An EZH2 inhibitor paired with a PI3K inhibitor showed no BAP1-related effect. The chosen doses were well tolerated in mice. In mice with implanted tumors (8 per group), single drugs had a modest effect, while the combination significantly reduced growth of BAP1-deficient tumors. In mice that developed mesothelioma in the chest (11 per group), the combination significantly increased survival and reduced tumor burden in the chest. With tazemetostat, median survival was 98 days versus 51 days with an inactive control treatment. The authors concluded the combination is worth testing in patients, and noted that how it works remains unclear.

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-line experiments (drug synergy and colony formation assays, RNA sequencing) and mouse experiments (tolerability study, tumor-implant (xenograft) models, and genetically engineered mice that develop mesothelioma)
• Who was studied: Mouse mesothelioma cell lines from genetically engineered mice with Bap1 deleted (BNC) or with Bap1 intact (NC); human mesothelioma cell lines (including BAP1-deficient NCI-H2731 and BAP1-proficient NCI-H2810); human uveal melanoma cell lines; NSG mice carrying implanted BNC or NC tumors (8 per treatment group); and genetically engineered mice that developed mesothelioma (BNC and BNCa models, 11 per treatment group). The work was done at the Netherlands Cancer Institute.
• Exposure: No asbestos exposure was studied. The study tested drug treatments: the EZH2 inhibitors GSK126 (40 mg/kg once daily by injection in mice) and tazemetostat (250 mg/kg twice daily by mouth), and the FGFR inhibitor AZD4547 (7.5 mg/kg once daily by mouth in tolerability and implanted-tumor experiments, 5 mg/kg in the genetically engineered mice). Each was given alone or combined.
• Main results:
  • In Bap1-deficient mouse mesothelioma cell lines, the GSK126 plus AZD4547 combination gave an overall synergy score above 30. In Bap1-proficient mouse lines, no synergy was observed.
  • In human mesothelioma cell lines, a high synergy score was seen in the BAP1-deficient line but not in the BAP1-proficient line.
  • In murine and human mesothelioma cell lines, drug concentrations with little or no effect alone led to an almost complete loss of cell survival when combined, only in BAP1-deficient lines.
  • In BNC cells, EZH2 inhibition raised the activity of FGF/FGFR-related genes. The authors suggested this might partially explain the synergy.
  • Combining GSK126 with the PI3K inhibitor BEZ-235 in human mesothelioma cell lines was not effective in all lines, and the effect could not be tied to BAP1 status.
  • In uveal melanoma cell lines, the combination's effect was restricted to BAP1-deficient lines.
  • The chosen drug doses were well tolerated in both immune-deficient and immune-competent mice, judged by body weight and survival.
  • In mice with implanted tumors (8 per group), single-agent GSK126 or AZD4547 had a modest effect on growth of both Bap1-proficient (NC) and Bap1-deficient (BNC) tumors.
  • In the same implanted-tumor mice, the GSK126 plus AZD4547 combination significantly reduced growth of BNC tumors.
  • With tazemetostat plus AZD4547, implanted BNC tumors showed pronounced reduction, but NC tumors did not.
  • In genetically engineered BNC mice that developed mesothelioma (11 per group), GSK126 plus AZD4547 significantly increased survival compared with control treatment (log-rank P less than 0.01).
  • In the same BNC mice, combination treatment significantly reduced tumor burden in the chest.
  • In a second engineered model (BNCa, 11 mice per group), median survival was 98 days with tazemetostat plus AZD4547 versus 51 days with control treatment.
• The authors' conclusion: The authors concluded that BAP1-deficient mesothelioma was sensitive to combined EZH2 and FGFR inhibition in their models. They considered this combination worth testing as a treatment for mesothelioma, and potentially other BAP1-mutated cancers.
• Limitations the authors state:
  • The authors stated that the precise mechanism by which BAP1-deficient cells are sensitized to the combination was not established and needs further investigation.

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: BAP1, Mesothelioma, Ipilimumab (Yervoy), Nivolumab (Opdivo), Biomarker, Immunotherapy, Prognosis, EZH2 Inhibitor.

Related studies

• Combination of EZH2 and ATM inhibition in BAP1-deficient mesothelioma — N. Landman, D. Hulsman, et al. (2024)
• Combined Genetic and Genealogic Studies Uncover a Large BAP1 Cancer Syndrome Kindred Tracing Back Nine Generations to a Common Ancestor from the 1700s — M. Carbone, E.G. Flores, et al. (2015)
• Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma — G.K. Pandey, N. Landman, et al. (2023)
• Combined deletion of Bap1, Nf2, and Cdkn2ab causes rapid onset of malignant mesothelioma in mice — J. Badhai, G.K. Pandey, et al. (2020)
• Dual Screen for Efficacy and Toxicity Identifies HDAC Inhibitor with Distinctive Activity Spectrum for BAP1-Mutant Uveal Melanoma — J.N. Kuznetsoff, D.A. Owens, et al. (2021)
• Comparison of Germline versus Somatic BAP1 Mutations for Risk of Metastasis in Uveal Melanoma — K.G. Ewens, E. Lalonde, et al. (2018)

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