TGFα Promotes Chemoresistance of Malignant Pleural Mesothelioma

Our plain-English summary of TGFα Promotes Chemoresistance of Malignant Pleural Mesothelioma, by B. Staumont, M. Jamakhani, C. Costa, et al (Cancers, 2020).

The study

• Authors: B. Staumont, M. Jamakhani, C. Costa, F. Vandermeers, S.N. Sriramareddy, G. Redouté, C. Mascaux, P. Delvenne, P. Hubert, R. Safari, L. Willems
• Journal: Cancers
• Published: 2020;12(6)
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: There is no standard chemotherapy for refractory or relapsing malignant pleural mesothelioma (MPM). Our previous reports nevertheless indicated that a combination of an anthracycline (doxorubicin) and a lysine deacetylase inhibitor (valproic acid, VPA) synergize to induce the apoptosis of MPM cells and reduce tumor growth in mouse models. A Phase I/II clinical trial indicated that this regimen is a promising therapeutic option for a proportion of MPM patients. Methods: The transcriptomes of mesothelioma cells were compared after Illumina HiSeq 4000 sequencing. The expression of differentially expressed genes was inhibited by RNA interference. Apoptosis was determined by cell cycle analysis and Annexin V/7-AAD labeling. Protein expression was assessed by immunoblotting. Preclinical efficacy was evaluated in BALB/c and NOD-SCID mice. Results: To understand the mechanisms involved in chemoresistance, the transcriptomes of two MPM cell lines displaying different responses to VPA-doxorubicin were compared. Among the differentially expressed genes, transforming growth factor alpha (TGFα) was associated with resistance to this regimen. The silencing of TGFα by RNA interference correlated with a significant increase in apoptosis, whereas the overexpression of TGFα desensitized MPM cells to the apoptosis induced by VPA and doxorubicin. The multi-targeted inhibition of histone deacetylase (HDAC), HER2 and TGFα receptor (epidermal growth factor receptor/EGFR) improved treatment efficacy in vitro and reduced tumor growth in two MPM mouse models. Finally, TGFα expression but not EGFR correlated with patient survival. Conclusions: Our data show that TGFα but not its receptor EGFR is a key factor in resistance to MPM chemotherapy. This observation may contribute to casting light on the promising but still controversial role of EGFR signaling in MPM therapy.

In plain English

This laboratory study, from the University of Liège, Belgium, looked at why some malignant pleural mesothelioma cells resist a drug combination of valproic acid (VPA) and doxorubicin. The authors compared gene activity in a cell line in which this treatment significantly increased cell death (M14K) and one in which it did not (H28). A growth-factor gene, TGFα, was among the most overexpressed genes in the resistant cells. Across 10 mesothelioma cell lines, higher TGFα went with less treatment-induced cell death (r = −0.6131, p = 0.0594, above the authors' 0.05 significance cut-off). Lowering TGFα increased cell death in H28 cells, and raising it reduced cell death in M14K cells. Adding gefitinib or erlotinib increased cell death in three cell lines, but the three-drug regimen was too toxic in mice. CUDC-101 plus doxorubicin reduced tumor growth in two mouse models. In public data on 87 mesothelioma patients, low TGFα was associated with better survival (p = 0.039). The EGFR result was not significant (p = 0.1). The authors concluded TGFα is a key factor in resistance and called for prospective trials.

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 using mesothelioma cell lines and mouse experiments, plus an analysis of a public patient gene-expression and survival dataset (TCGA)
• Who was studied: Ten human mesothelioma cell lines (M14K, M38K, MSTO-211H, NCI-H2452, H28, SPC111, SPC212, ZL34, ZL5, ZL55) and murine AB12 cells. BALB/c and NOD-SCID mice, six per group. A TCGA dataset of 87 mesothelioma patients. Work done at the University of Liège, Belgium.
• Exposure: No asbestos exposure was studied. The exposures were drug treatments: valproic acid (2 mM), doxorubicin (100 nM), the EGFR inhibitors gefitinib and erlotinib (3 μM each), and CUDC-101 (1 μM) in cells. In mice: CUDC-101 at 100 mg/kg twice weekly and/or doxorubicin at 0.5 mg/kg once weekly. TGFα levels were also lowered or raised genetically.
• Main results:
  • Doxorubicin plus VPA significantly induced cell death (apoptosis) in M14K cells but not in H28 cells.
  • TGFα was among the top overexpressed genes in the resistant H28 cells compared with M14K cells, with a log2 fold change greater than 6.
  • Across 10 mesothelioma cell lines, TGFα level was negatively correlated with apoptosis induced by doxorubicin-VPA (r = −0.6131). The printed p-value was 0.0594.
  • Inhibiting TGFα expression made H28 cells more sensitive to doxorubicin-VPA (p less than 0.01).
  • Increasing TGFα expression significantly decreased doxorubicin-VPA-induced apoptosis in M14K cells.
  • Gefitinib or erlotinib added to doxorubicin and VPA increased apoptosis in three cell lines (M14K, H28, ZL34). The three-drug regimen was not well tolerated in mice because of excessive toxicity (data not shown).
  • In mice, neither CUDC-101 nor doxorubicin alone showed antitumor activity compared with vehicle. The combination reduced tumor growth in both mouse models.
  • In the TCGA patient data, low TGFα expression was associated with better survival (p = 0.039). A similar trend for EGFR was not statistically significant (p = 0.1).
• The authors' conclusion: The authors concluded that TGFα is a key factor in the resistance of malignant pleural mesothelioma to doxorubicin. They stated that whether TGFα can serve as a prognostic factor or treatment target needs validation in prospective trials.
• Limitations the authors state:
  • The authors stated that the value of TGFα as a prognostic factor or therapeutic target still needs validation in prospective trials.
  • The authors stated that the toxicity and efficacy of CUDC-101 plus doxorubicin have yet to be evaluated in clinical trials with mesothelioma patients.
  • The authors noted that the value of any treatment combination must be clearly demonstrated, including defining which patients would benefit most.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Chemotherapy, Doxorubicin, Apoptosis, Clinical Trial, Mesothelioma, HER2, EGFR.

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