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Translational Therapeutics

Efficacy of CDK4/6 inhibitors in preclinical models of malignant pleural mesothelioma

British Journal of Cancer volume 125, pages 1365–1376 (2021)Cite this article

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Abstract

Background

There is no effective therapy for patients with malignant pleural mesothelioma (MPM) who progressed to platinum-based chemotherapy and immunotherapy.

Methods

We aimed to investigate the antitumor activity of CDK4/6 inhibitors using in vitro and in vivo preclinical models of MPM.

Results

Based on publicly available transcriptomic data of MPM, patients with CDK4 or CDK6 overexpression had shorter overall survival. Treatment with abemaciclib or palbociclib at 100 nM significantly decreased cell proliferation in all cell models evaluated. Both CDK4/6 inhibitors significantly induced G1 cell cycle arrest, thereby increasing cell senescence and increased the expression of interferon signalling pathway and tumour antigen presentation process in culture models of MPM. In vivo preclinical studies showed that palbociclib significantly reduced tumour growth and prolonged overall survival using distinct xenograft models of MPM implanted in athymic mice.

Conclusions

Treatment of MPM with CDK4/6 inhibitors decreased cell proliferation, mainly by promoting cell cycle arrest at G1 and by induction of cell senescence. Our preclinical studies provide evidence for evaluating CDK4/6 inhibitors in the clinic for the treatment of MPM.

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Fig. 1: Quantification of the expression levels of key cell cycle regulators and response to treatment with CDK4/6 inhibitors in a panel of commercial MPM cell lines and primary patient-derived cultures.
Fig. 2: Effects of CDK4/6 inhibitors in cell cycle and cell senescence in MPM cell lines.
Fig. 3: In vivo treatment with palbociclib in MSTO-211H subcutaneous xenografted MPM model.
Fig. 4: In vivo treatment with CDK4/6 inhibitors in advanced orthotopic MPM models.
Fig. 5: Overall survival analysis according to CDK4 and CDK6 expression in two cohorts of patients with MPM.

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Data availability

All data generated or analysed during this study will be stored in EGA and available on reasonable request.

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Acknowledgements

We thank CERCA Programme/Generalitat de Catalunya for their institutional support and grant 2017SGR448.

Funding

EN received support from the SLT006/17/00127 grant, funded by the Department of Health of the Generalitat de Catalunya by the call “Acció instrumental d’intensificació de professionals de la salut”. This study was supported by grants from Instituto de Salud Carlos III (grants PI14/01109 and PI18/00920) (co-funded by European Regional Development Fund. ERDF, a way to build Europe), Spanish Society of Medical Oncology grant for emerging research groups and from Pfizer (WI244174) to EN. MH-M was supported by a Marie Skłodowska-Curie grant, agreement no. 766214.

Author information

Authors and Affiliations

  1. Preclinical and Experimental Research in Thoracic Tumors (PrETT) group. Oncobell Program. Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat (Barcelona), Barcelona, Spain

    Elisabet Aliagas, Ania Alay, Miguel Hernández-Madrigal, David Cordero, Mireia Gausachs, Ramón Palmero, Cristina Muñoz-Pinedo, Xavi Solé & Ernest Nadal

  2. Unit of Bioinformatics for Precision Oncology, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat (Barcelona), Barcelona, Spain

    Ania Alay, David Cordero & Xavi Solé

  3. Chemoresistance group. Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat (Barcelona), Barcelona, Spain

    Maria Martínez-Iniesta & Alberto Villanueva

  4. Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Barcelona, Spain

    David Cordero & Xavi Solé

  5. Cancer Genetics Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Badalona, Barcelona, Spain

    Eva Pros, Maria Saigí & Montse Sánchez-Céspedes

  6. Department of Genetics and Genome Biology, Leicester Cancer Research Centre, University of Leicester, Leicester, UK

    Sara Busacca & Dean Fennell

  7. University of Sheffield Teaching Hospitals, Sheffield, UK

    Annabel J. Sharkley

  8. Department of Thoracic Surgery, Glenfield Hospital, Leicester, UK

    Alan Dawson

  9. Department of Medical Oncology, Catalan Institute of Oncology, L’Hospitalet de Llobregat (Barcelona), Barcelona, Spain

    Ramón Palmero, José C. Ruffinelli & Ernest Nadal

  10. Department of Respiratory Medicine, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat (Barcelona), Barcelona, Spain

    Susana Padrones & Samantha Aso

  11. Department of Thoracic Surgery, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat (Barcelona), Barcelona, Spain

    Ignacio Escobar & Ricard Ramos

  12. Department of Pathology, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat (Barcelona), Barcelona, Spain

    Roger Llatjós, August Vidal, Eduard Dorca & Mar Varela

  13. Mesothelioma Research Programme, Department of Genetics and Genome Biology, University of Leicester, Leicester, UK

    Dean Fennell

  14. Department of Clinical Sciences, School of Medicine and Health Sciences, Universitat de Barcelona, L’Hospitalet del Llobregat (Barcelona), Campus Bellvitge, Barcelona, Spain

    Ernest Nadal

Authors
  1. Elisabet Aliagas
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  2. Ania Alay
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  3. Maria Martínez-Iniesta
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  4. Miguel Hernández-Madrigal
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  5. David Cordero
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  6. Mireia Gausachs
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  7. Eva Pros
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  8. Maria Saigí
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  9. Sara Busacca
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  10. Annabel J. Sharkley
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  11. Alan Dawson
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  12. Ramón Palmero
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  13. José C. Ruffinelli
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  14. Susana Padrones
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  15. Samantha Aso
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  16. Ignacio Escobar
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  17. Ricard Ramos
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  18. Roger Llatjós
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  19. August Vidal
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  20. Eduard Dorca
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  21. Mar Varela
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  22. Montse Sánchez-Céspedes
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  23. Dean Fennell
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  24. Cristina Muñoz-Pinedo
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  25. Alberto Villanueva
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  26. Xavi Solé
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  27. Ernest Nadal
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Contributions

EA: conceptualisation, methodology, validation, formal analysis, investigation, resources, data curation, writing—original draft, writing—review and editing, visualisation. AA: conceptualisation, software, validation, formal analysis, resources, data curation, writing—review and editing, visualisation. MM-I: methodology, investigation, resources, data curation. MH-M: methodology, validation, investigation, data curation. DC: conceptualisation, software, validation, formal analysis, data curation. MG: conceptualisation, resources, writing—review and editing. EP: resources, writing—review and editing. MS: resources, writing—review and editing. SB: software, validation, data curation. AJS: resources, writing—review and editing. AD: resources, writing—review and editing. RP: resources, data curation, writing—review and editing. SP: resources, writing—review and editing. SA: resources, writing—review and editing. IE: resources, writing—review and editing. RR: resources, writing—review and editing. RL: resources, validation, data curation. AV: resources, validation, data curation. ED: data curation. MV: resources, validation, data curation. MS-C: resources, writing—review and editing. DF: resources, validation, formal analysis, investigation, data curation, writing—review and editing. CM-P: conceptualisation, methodology, validation, formal analysis, investigation, data curation, writing—review and editing, visualisation. AV: conceptualisation, methodology, validation, formal analysis, investigation, data curation, writing—review and editing, visualisation. XS: conceptualisation, software, formal analysis, data curation, writing—review and editing, visualisation. EN: conceptualisation, methodology, validation, formal analysis, investigation, resources, data curation, writing—original draft, writing—review and editing, visualisation, supervision, project administration, funding acquisition.

Corresponding author

Correspondence to Ernest Nadal.

Ethics declarations

Competing interests

EN received research support from Roche, Pfizer, Bristol Myers Squibb and Merck Serono and participated in advisory boards from Bristol Myers Squibb, Merck Serono, Merck Sharpe & Dohme, Lilly, Roche, Pfizer, Takeda, Boehringer Ingelheim, Bayer, Amgen and Astra Zeneca. RP has participated in advisory boards from Bristol Myers Squibb, Merck Sharpe & Dohme, Roche, Pfizer, Lilly, Boehringer Ingelheim and Astra Zeneca. DF has received research support from Astex Therapeutics, Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Merck Sharpe & Dohme, Lilly Oncology, Roche and participated in advisory boards from Atara Therapeutics, Bayer, Boehringer Ingelheim and Inventiva. The other authors declare no competing interests.

Ethics approval and consent to participate

The retrospective cohort was approved by a National Ethical Committee, under the references 4/LO/1527 (a translational research platform entitled Predicting Drug and Radiation Sensitivity in Thoracic Cancers—also approved by University Hospitals of Leicester NHS Trust under the reference IRAS131283) and 14/EM/1159 (retrospective cohort). Pleural effusions samples were obtained after patients signed the informed consent approved by the Hospital de Bellvitge Ethical Committee (PR152/14). All the animal experiments were performed in accordance with protocols approved by Animal Research Ethics Committee at IDIBELL. This study was performed in accordance with the principles outlined in the Declaration of Helsinki.

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Aliagas, E., Alay, A., Martínez-Iniesta, M. et al. Efficacy of CDK4/6 inhibitors in preclinical models of malignant pleural mesothelioma. Br J Cancer 125, 1365–1376 (2021). https://doi.org/10.1038/s41416-021-01547-y

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