Areso Zubiaur, Itziar Ibone;
(2020)
Pro-apoptotic TRAIL- and CDK9 inhibition-based cancer therapy.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
TRAIL was shown to specifically kill cancer cells in vivo without causing toxicity. Based on this, TRAIL-R agonists were developed for clinical use. However, to date, TRAIL-R agonists have only shown limited therapeutic benefit in clinical trials. This is likely attributed to the fact that most primary human cancers are TRAIL-resistant. It is therefore essential to identify potent and cancer-selective TRAIL-sensitising drugs that overcome TRAIL-resistance. In this thesis it is shown that the CDK9 inhibitor Dinaciclib broadly sensitises different cancer types to TRAIL-induced apoptosis, including, notably, chemo- and targeted therapy-resistant tumour cells. Mechanistically, treatment with Dinaciclib results in RNA polymerase II inhibition, leading to the inhibition of transcriptional elongation. Consequently, this induces the downregulation of FLIP and Mcl-1, two anti-apoptotic proteins that are frequently upregulated in TRAIL-resistant cancer cells. Furthermore, this thesis shows that Dinaciclib, in addition to CDK9, also targets the transcriptional regulator BRD4, and that the combined inhibition of both is required to break TRAIL-resistance in several cancer cell lines. Moreover, this thesis demonstrates that the combination of TRAIL and Dinaciclib has therapeutic efficacy in different mouse models of NSCLC, including the Kras and Tp53-driven KP autochthonous mouse model, which recapitulates the histopathological features of the human disease. This combination led to significant tumour regression and prolonged the survival of these mice. Additionally, the effect of this novel combination on the tumour microenvironment was explored. It was found that for its in-vivo activity, Dinaciclib requires the action of the adaptive immune system. Lastly, I propose the development of novel immunogenic mouse models of NSCLC that resemble the mutational burden of human tumours by combining the cancer cell-specific expression of oncogenic drivers with the administration of carcinogens. In conclusion, this thesis validates the combined use of TRAIL and Dinaciclib as a potent cancer therapy.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Pro-apoptotic TRAIL- and CDK9 inhibition-based cancer therapy |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10094082 |
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