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The role of oncogenic KRAS in the immune evasion of non-small cell lung cancer

Mugarza Strobl, Edurne; (2021) The role of oncogenic KRAS in the immune evasion of non-small cell lung cancer. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Lung cancer is a highly mutated tumour type in which, if effective, cancer immunotherapies have proven to be superior to other treatment modalities. However, tumours develop mechanisms by which they are able to evade the actions of the immune system, some of which may render them unresponsive to drugs aimed to boost antitumor immunity. KRAS is the most frequently mutated oncogene in cancer. Activating mutations in KRAS are found in up to a third of all lung cancer patients and have been previously shown to trigger immunosuppressive actions by tumour cells. Approximately a third of KRAS-mutant lung cancer patients harbour G12C mutations, which are amenable to therapeutic targeting thanks to the development of novel KRASG12C inhibitors, which are currently being tested in clinical trials. In this study, we aim to unveil new immunosuppressive mechanisms triggered by oncogenic KRAS signalling in vitro and in clinically relevant mouse models. Additionally, we try to elucidate the effects of novel KRASG12C inhibitors on the tumour microenvironment, with the ultimate goal of developing rational combination therapies. Using human cell lines, we have generated a gene expression dataset of KRAS-dependent genes. We have also developed a modified version of the murine lung cancer cell line 3LL to be able to perform experiments in an in vivo setting. Making use of these tools, we have established a link between KRAS signalling and the recruitment of immunosuppressive myeloid cells to the tumour microenvironment. Furthermore, the use of a therapeutic compound against KRASG12C has shown profound changes in the tumour microenvironment, further underscoring the fact that KRAS signalling can be immunosuppressive. This study highlights the possibility of therapeutically targeting components of the tumour microenvironment in KRAS mutant lung cancer, in combination with standard of care treatments or novel therapies such as KRASG12C inhibitors.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The role of oncogenic KRAS in the immune evasion of non-small cell lung cancer
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/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 Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10127453
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