Gene expression profiling of homologous recombination repair pathway indicates susceptibility for olaparib treatment in malignant pleural mesothelioma in vitro

Our plain-English summary of Gene expression profiling of homologous recombination repair pathway indicates susceptibility for olaparib treatment in malignant pleural mesothelioma in vitro, by S. Borchert, M. Wessolly, J. Schmeller, et al (BMC Cancer, 2019).

The study

• Authors: S. Borchert, M. Wessolly, J. Schmeller, E. Mairinger, J. Kollmeier, T. Hager, T. Mairinger, T. Herold, D.C. Christoph, R.F.H. Walter, W.E.E. Eberhardt, T. Plönes, J. Wohlschlaeger, C. Aigner, K.W. Schmid, F.D. Mairinger
• Journal: BMC Cancer
• Published: 2019;19(1):108
• Cited by: 31 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a tumour arising from pleural cavities with poor prognosis. Multimodality treatment with pemetrexed combined with cisplatin shows unsatisfying response-rates of 40%. The reasons for the rather poor efficacy of chemotherapeutic treatment are largely unknown. However, it is conceivable that DNA repair mechanisms lead to an impaired therapy response. We hypothesize a major role of homologous recombination (HR) for genome stability and survival of this tumour. Therefore, we analysed genes compiled under the term "BRCAness". An inhibition of this pathway with olaparib might abrogate this effect and induce apoptosis.

Methods: We investigated the response of three MPM cell lines and lung fibroblasts serving as a control to treatment with pemetrexed, cisplatin and olaparib. Furthermore, we aimed to find possible correlations between response and gene expression patterns associated with BRCAness phenotype. Therefore, 91 clinical MPM samples were digitally screened for gene expression patterns of HR members.

Results: A BRCAness-dependent increase of apoptosis and senescence during olaparib-based treatment of BRCA-associated-protein 1 (BAP1)-mutated cell lines was observed. The gene expression pattern identified could be found in approx. 10% of patient samples. Against this background, patients could be grouped according to their defects in the HR system. Gene expression levels of Aurora Kinase A (AURKA), RAD50 as well as DNA damage-binding protein 2 (DDB2) could be identified as prognostic markers in MPM.

Conclusions: Defects in HR compiled under the term BRCAness are a common event in MPM. The present data can lead to a better understanding of the underlaying cellular mechanisms and leave the door wide open for new therapeutic approaches for this severe disease with infaust prognosis. Response to Poly (ADP-ribose)-Polymerase (PARP)-Inhibition could be demonstrated in the BAP1-mutated NCI-H2452 cells, especially when combined with cisplatin. Thus, this combination therapy might be effective for up to 2/3 of patients, promising to enhance patients' clinical management and outcome.

In plain English

This laboratory study also retrospectively analysed patients' tumour samples; it did not examine asbestos exposure. The authors treated three malignant pleural mesothelioma (MPM) cell lines and a lung fibroblast control line with pemetrexed, cisplatin and olaparib, alone or combined. Olaparib caused no apoptosis (programmed cell death) in the control or MSTO-211H cells. The authors identified BAP1-mutant NCI-H2452 as responding to olaparib with apoptosis. Olaparib alone gave a 30 to 50% senescence signal in NCI-H2052, a line the article elsewhere calls olaparib-responsive. In NCI-H2452, olaparib with cisplatin gave an apoptosis signal of about 70% of a positive control's signal, normalized to untreated cells. Gene expression was then measured in tumour samples from 90 MPM patients treated with cisplatin and pemetrexed (91 in one table and the abstract). About 10% of samples shared the NCI-H2452 pattern. Low AURKA and high DDB2 expression were associated with longer overall survival. The article contradicts itself on whether high RAD50 expression meant longer or shorter survival. The authors concluded that olaparib with cisplatin "might be effective for up to 2/3 of patients", though olaparib was tested only on cells, not on patients.

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) cell-line drug experiment combined with retrospective gene-expression analysis of stored patient tumour samples
• Who was studied: Three MPM cell lines (MSTO-211H, NCI-H2052 and BAP1-mutant NCI-H2452) and the lung fibroblast control line MRC-5. Also tumour samples from MPM patients treated in Essen (2006 to 2009) and Berlin (2002 to 2009), all given first-line cisplatin and pemetrexed. The Methods give 90 samples (46 from Berlin, 44 from Essen); Table 2 and the abstract give 91.
• Exposure: Drug treatment of cells: pemetrexed 0.25 micromolar, cisplatin 10 micromolar, and olaparib at 0.1 to 10 micromolar, alone or with cisplatin. Asbestos exposure was not studied.
• Main results:
  • In the MRC-5 control cells and MSTO-211H mesothelioma cells, olaparib produced no apoptosis.
  • The results text names BAP1-mutant NCI-H2452 as the cell line responding to olaparib, with apoptosis during olaparib-based treatment.
  • In NCI-H2052 cells, olaparib alone at 1 and 10 micromolar induced a 30 to 50% senescence signal. Elsewhere the article calls NCI-H2052 olaparib-responsive.
  • In NCI-H2452 cells, olaparib combined with cisplatin gave a 70% apoptosis signal and a 20% senescence signal. These values are percentages of the positive-control signal, normalized to untreated cells, not percentages of cells. The figure legend lists 0.5, 1 or 10 micromolar olaparib; the results text names only 0.5 and 1 micromolar.
  • The gene expression pattern of NCI-H2452 cells was found in approximately 10% of patient samples.
  • Unsupervised clustering split patient samples into two groups of about half each. The group with altered homologous recombination repair contained 49 samples.
  • AURKA, RAD50 and DDB2 gene expression were significantly associated with overall survival, with false-discovery-rate-adjusted p-values of 0.02 or less.
  • Patients with low AURKA expression had a 2.4-fold higher chance of prolonged overall survival.
  • Low AURKA expression was also associated with a 2.3-fold higher chance of prolonged progression-free survival.
  • Patients with high DDB2 expression showed a 4.373-fold chance of prolonged survival.
  • The results text says high RAD50 expression meant a 2.3-fold higher risk of dying. The Figure 5 legend and the discussion instead say high RAD50 expression was associated with prolonged survival.
  • Gene expression patterns did not differ significantly by tumour histology (biphasic, epithelioid, sarcomatoid).
• The authors' conclusion: The authors concluded that olaparib combined with cisplatin might be effective for up to two-thirds of MPM patients. They also concluded that the gene expression patterns are a promising tool for predicting response to olaparib.

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, Prognosis, Pemetrexed (Alimta), Cisplatin, Apoptosis, Fibroblast, BAP1.

Related studies

• Assessing the function of homologous recombination DNA repair in malignant pleural effusion (MPE) samples — M.J. Patterson, R.E. Sutton, et al. (2014)
• Cancer-Associated Fibroblasts Influence Survival in Pleural Mesothelioma: Digital Gene Expression Analysis and Supervised Machine Learning Model — S. Borchert, A. Mathilakathu, et al. (2023)
• The Association of BAP1 Loss-of-Function With the Defect in Homologous Recombination Repair and Sensitivity to PARP-Targeted Therapy — H. Yang, D. Xu, et al. (2020)
• Impact of metallothionein-knockdown on cisplatin resistance in malignant pleural mesothelioma — S. Borchert, P.M. Suckrau, et al. (2020)
• An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression — T.T.T. Nguyen, M. Shingyoji, et al. (2021)
• Mitogen signal-associated pathways, energy metabolism regulation, and mediation of tumor immunogenicity play essential roles in the cellular response of malignant pleural mesotheliomas to platinum-based treatment: a retrospective study — A. Mathilakathu, S. Borchert, et al. (2021)

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