Bortezomib sensitivity is tissue dependent and high expression of the 20S proteasome precludes good response in malignant pleural mesothelioma

Our plain-English summary of Bortezomib sensitivity is tissue dependent and high expression of the 20S proteasome precludes good response in malignant pleural mesothelioma, by R.F.H. Walter, S.R. Sydow, E. Berg, et al (Cancer Management and Research, 2019).

The study

• Authors: R.F.H. Walter, S.R. Sydow, E. Berg, J. Kollmeier, D.C. Christoph, S. Christoph, W.E.E. Eberhardt, T. Mairinger, J. Wohlschlaeger, K.W. Schmid, F.D. Mairinger
• Journal: Cancer Management and Research
• Published: 2019;11:8711-8720
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Bortezomib is an approved proteasome inhibitor for the treatment of certain lymphoma subtypes. Two clinical trials investigated bortezomib in patients with malignant pleural mesothelioma (MPM) and failed to improve outcome. We present a potential explanation for this event.

Methods: 171 patients with MPM were analyzed for their mRNA expression of proteasomal subunits PSMA1, PSMA5, PSMB1, PSMB2, PSMB4 and PSMB5 via qPCR (n=84) or sequencing (n=87 TCGA/cBioPortal data set "Mesothelioma"). Outcome and subunit expression were correlated. Four mesothelial and one fibroblast cell line were treated with bortezomib and cisplatin. Cellular response was measured after 0, 6, 12, 24, 48 and 72 hrs. Enzyme activity of proteasomal subunits was assessed via functional enzyme activity assays.

Results: Patients with MPM presented with elevated expression of proteasomal subunits compared to benign controls (p<0.001). PSMB4 correlated with outcome (Cox propotiortional-hazards model (COXPH): p<0.0175, TCGA/cBioPortal data). In cell lines, apoptosis was the main event with a peak after 48 hr incubation for bortezomib or cisplatin. Only two cell lines with comparably low proteasome activity (PSMB2 and PSMB5) responded to 50 nM and 100 nM bortezomib better than to cisplatin (MRC-5, NCI-H2052). MSTO-211H responded to cisplatin only, whereas the other two cell lines were considered therapy resistant (Met-5A, NCI-H2452).

Interpretation: Two clinical trials testing bortezomib in MPM failed, although MPM presents with high proteasome expression, which predicts bortezomib sensitivity in several tumors. Bortezomib induced apoptosis in MPM cell lines with low proteasome activity only. Bortezomib is not suitable for the treatment of MPM, and biomarker-based stratification could have improved both clinical trials.

Trial Registration: NCT00513877 and NCT00458913.

© 2019 Walter et al.

In plain English

This retrospective German study asked why two earlier bortezomib trials, run by other researchers, failed to improve outcomes in malignant pleural mesothelioma. It did not study asbestos exposure. The authors measured how active the genes for the proteasome are; the proteasome is a protein-recycling system that bortezomib blocks. They tested tumor samples from 84 patients and public data on 87 more. Five of these genes were more active in mesothelioma than in benign tissue from patients with spontaneous pneumothorax (a collapsed lung), all p less than 0.001. In the public data, PSMB4 expression was linked with survival (p less than 0.0175; 56 patients had survival data). No gene was linked with survival in the authors' own patients. In lab-grown cells, bortezomib caused the most apoptosis (programmed cell death) in one mesothelioma line and one benign lung fibroblast line. These were the two lines with the lowest PSMB2 and PSMB5 enzyme activity. The authors concluded that bortezomib is not suitable for this cancer. They suggested that high proteasome expression predicts poor response. They noted that none of the significant links between gene expression and clinical features would survive correction for multiple testing.

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, exploratory biomarker study of tumor samples and a public dataset, combined with laboratory cell line experiments
• Who was studied: Archived tumor samples from 84 patients with malignant pleural mesothelioma: 40 from Helios Hospital Emil von Behring, Berlin, and 44 from University Hospital Essen, Germany. All patients had first-line cisplatin plus pemetrexed, in Essen between 2006 and 2009 or in Berlin between 2002 and 2009. The study also used 87 patients from the TCGA/cBioPortal 'Mesothelioma' dataset (survival data for 56) and benign control tissue from patients with spontaneous pneumothorax. Five cell lines were tested: three MPM lines (MSTO-211H, NCI-H2452, NCI-H2052), one SV40-immortalized mesothelial line (MeT-5A) and one benign lung fibroblast line (MRC-5).
• Exposure: No asbestos exposure was studied. The study measured expression of proteasome subunits (PSMA1, PSMA5, PSMB1, PSMB2, PSMB4, PSMB5, PSMD1) and treated cell lines with bortezomib (50 nM and 100 nM) and cisplatin.
• Main results:
  • In tumors, expression of PSMA1, PSMA5, PSMB4, PSMB5 and PSMD1 was significantly higher than in benign control tissue (all p less than 0.001). PSMB1 and PSMB2 were not measured in the controls.
  • In the authors' own 84 patients, progression status correlated with PSMB1 (p=0.004) and PSMB5 (p=0.027).
  • In the authors' own patients, proteasome subunit expression did not correlate with overall or progression-free survival.
  • In the TCGA/cBioPortal data (survival data for 56 patients), PSMB4 expression correlated with outcome in a Cox model (p less than 0.0175). No other subunit correlated with survival.
  • In the cell lines, apoptosis (programmed cell death) was the main effect, with the optimal time point at 48 hours. Bortezomib at 50 nM and 100 nM caused the highest induction of apoptosis in NCI-H2052 (an MPM line) and MRC-5 (a benign fibroblast line). These two lines had the lowest PSMB2 and PSMB5 enzyme activity and were not affected by cisplatin.
  • The other three lines responded differently. MSTO-211H responded to cisplatin, with a negligible response to the other drugs. NCI-H2452 showed a slight response only to 100 nM bortezomib. MeT-5A responded equally to all cytostatics.
• The authors' conclusion: The authors concluded that bortezomib is not suitable for the treatment of MPM and that biomarker-based selection of patients could have improved both earlier trials. They suggested that bortezomib sensitivity is tissue dependent and that elevated proteasome expression is a negative predictor of therapy response in MPM.
• Limitations the authors state:
  • None of the statistically significant associations between proteasome subunit expression and clinicopathological parameters (such as survival and progression status) would pass a false-discovery adjustment. No such adjustment was performed.
  • The study design rests mostly on how cell lines responded to treatment and does not reflect the full complexity of the question, for example effects on immune proteasome activity.
  • The authors state it remains unclear why high proteasome subunit expression is not directly associated with sensitivity to bortezomib.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Clinical Trial, Mesothelioma, Fibroblast, Cisplatin, Apoptosis, Biomarker.

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