Dual HDAC and PI3K Inhibitor CUDC-907 Inhibits Growth of Pleural Mesothelioma: The Impact of Cisplatin Sensitivity and Myc Expression

Our plain-English summary of Dual HDAC and PI3K Inhibitor CUDC-907 Inhibits Growth of Pleural Mesothelioma: The Impact of Cisplatin Sensitivity and Myc Expression, by L. Hegedüs, S. Qaisieh, C. Stülpnagel, et al (Cells, 2025).

The study

• Authors: L. Hegedüs, S. Qaisieh, C. Stülpnagel, Y. Ganjeh Khor Dezfouli, W. Tambo, F. Doerr, N. Baldes, D. Theegarten, M. Schuler, S. Bölükbas, B. Hegedüs
• Journal: Cells
• Published: 2025;14(20)
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Objectives: Pleural mesothelioma (PM) is a rare cancer that often develops after a decades-long latency period and confers a grim prognosis. Novel, biomarker-based therapeutic modalities are expected to improve the outcome of patients with advanced PM. CUDC-907 (fimepinostat) is a dual inhibitor that affects both histone deacetylases and PI3K enzymes. Its antitumor activity was described in several cancer types, but it has not yet been explored in PM. Materials and Methods: The sensitivity of 22 PM cell lines-including 18 models established in our laboratory-to cisplatin and CUDC-907 was determined using a cell viability assay. BAP1, PTEN, and c-Myc expression, as well as MYC copy number variation, were measured. The effect of combination treatment with cisplatin was assessed with cell viability, cell cycle, and 3D spheroid formation assays. Results: Most PM cell lines were sensitive to CUDC-907 treatment, and the CUDC-907 response was significantly higher in cell lines with higher c-Myc expression due to MYC copy number gain or amplification. Importantly, all cisplatin-insensitive cell lines were sensitive to CUDC-907. Combination treatment with cisplatin synergistically decreased cell viability and induced G2/M arrest or cell death. We tested cisplatin-sensitive P31WT and cisplatin resistant P31cis isogeneic pair and found that in both 2D and 3D assays the cisplatin-resistant cells showed a higher sensitivity to CUDC-907 single treatment. Combining CUDC-907 with cisplatin further decreased cell growth even in cisplatin-resistant cells. Conclusions: The majority of PM cell models are sensitive to CUDC-907, which may be a potent therapeutic agent in PM.

In plain English

This laboratory study used pleural mesothelioma cells; no patients were treated. The authors tested an experimental drug, CUDC-907 (fimepinostat), alone and with the chemotherapy drug cisplatin. They used 22 pleural mesothelioma cell lines, 18 established in their laboratory from patients' pleural effusion (fluid around the lungs). In 17 of 20 cell lines first tested, the drug strongly reduced cell viability, and three lines were less sensitive. Cell lines with extra copies of the MYC gene were significantly more sensitive. All cisplatin-insensitive cell lines were sensitive to CUDC-907. Combining the drugs was synergistic in the three cell lines tested this way. In a related pair of cell lines, the cisplatin-resistant one was slightly more sensitive to CUDC-907 in flat cultures and more clearly so in three-dimensional cell clusters (spheroids). In that resistant line the combination was additive rather than synergistic. The authors concluded that CUDC-907 might be a potent agent in pleural mesothelioma treatment. The authors described their cell-line panel as representative in terms of asbestos exposure, among other features, but did not test whether exposure affected drug response.

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 (in vitro) study of human pleural mesothelioma cell lines, using 2D cell cultures and 3D spheroids
• Who was studied: 22 pleural mesothelioma cell lines. 18 were established in the authors' laboratory at University Medicine Essen, Germany, from the pleural effusion of pleural mesothelioma patients. The others were SPC111, SPC212, and the P31 wild-type line with its cisplatin-resistant partner (P31 cis). The authors stated that the panel is representative of general mesothelioma cohorts in gender, age, asbestos exposure and histotype distribution.
• Exposure: The drug CUDC-907 alone (1 nM to 0.3 µM for 72 hours) and in combination with cisplatin (CUDC-907 at 1, 10, 30 or 50 nM with cisplatin at 2, 4, 6 or 8 µM). Whether asbestos exposure affected drug response was not tested.
• Main results:
  • Of 20 pleural mesothelioma cell lines in the main sensitivity test, CUDC-907 strongly reduced cell viability in 17.
  • Three of these cell lines were substantially less sensitive. For them, the concentration that halved cell viability (IC50) was around 100 nM.
  • Loss of BAP1 or PTEN was not significantly correlated with CUDC-907 sensitivity.
  • Seven cell lines had MYC copy number gain (4 or more copies). Three had amplification (6 or more copies).
  • Cell lines with MYC copy number gain or amplification had significantly lower CUDC-907 IC50 values, meaning higher sensitivity, than cell lines with normal copy number (p = 0.0183).
  • Cell lines with higher c-Myc protein expression had lower sensitivity to cisplatin, but the difference was not statistically significant (p = 0.1187).
  • All cisplatin-insensitive cell lines were sensitive to CUDC-907. The three cell lines with low CUDC-907 sensitivity were sensitive to cisplatin.
  • In six cell lines examined further, c-Myc protein expression was reduced by CUDC-907 treatment in all of them.
  • In three cell lines with moderate sensitivity to both drugs (PF561, PF760, PF774), combining CUDC-907 with cisplatin had a synergistic effect on cell viability.
  • In the P31 cell line pair (cisplatin IC50 of 4.4 µM for P31 WT and 38 µM for the resistant P31 cis), the cisplatin-resistant cells were slightly more sensitive to CUDC-907 in the 2D viability assay. The CUDC-907 IC50 was 16 nM for P31 WT and 12 nM for P31 cis. The difference was significant at the 10 nM treatment.
  • In 3D spheroids, the difference between the P31 pair was more pronounced. Cell viability was significantly reduced in the cisplatin-resistant cells at 10, 30 and 50 nM CUDC-907, and spheroid volume decreased more.
  • The CUDC-907 and cisplatin combination had a strong synergistic effect on cell viability in the parental P31 cells and an additive effect in the cisplatin-resistant P31 cis cells.
• The authors' conclusion: The authors concluded that most pleural mesothelioma cell lines are sensitive to CUDC-907 and that combining it with cisplatin can lead to synergistic effects. For this reason, CUDC-907 might be a potent agent in pleural mesothelioma treatment. They wrote that their findings provide a rationale for clinical exploration.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Cisplatin, Latency, Prognosis, Biomarker, BAP1.

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