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Characterising EGFR tyrosine kinase inhibitor-adapted non-small cell lung cancer cell lines

Kuerten, Timo Leopold (2019) Characterising EGFR tyrosine kinase inhibitor-adapted non-small cell lung cancer cell lines. Master of Science by Research (MScRes) thesis, University of Kent,. (Access to this publication is currently restricted. You may be able to access a copy if URLs are provided) (KAR id:80550)

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Language: English

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Abstract

Tyrosine kinase inhibitors (TKIs) that target the human epidermal growth factor receptor (EGFR) are targeted therapies used in the clinic for treating non-small cell lung cancer (NSCLC) harbouring activating mutations in the EGFR protein. As a targeted therapy, EGFR TKIs offer several benefits over broad-spectrum general chemotherapy, mainly through increased efficacy and a reduction in adverse side effects. However, acquired drug resistance to EGFR TKIs is a pervasive issue, leading to the development of several generations of these drugs in an attempt to overcome it. Unfortunately, due to a variety of distinct mechanisms, acquired resistance inevitably manifests itself after treatment with each new generation of inhibitors. The aim of this project was therefore to characterise HCC827 and HCC4006 NSCLC cell lines that had each been drug-adapted to erlotinib, gefitinib or afatinib by examining their morphology, growth and response to a drug panel comprised of 5 anti-cancer drugs with varying mechanisms of action - paclitaxel, osimertinib, trametinib, cabozantinib and dichloroacetate. The characterisation process highlighted the strong heterogeneity associated with acquired drug resistance - despite being derived from the same tissue and NSCLC subtype (adenocarcinoma) as well as harbouring very similar EGFR-activating mutations, the morphology, growth and drug response rates between HCC827 and HCC4006 cells adapted to the same EGFR TKI showed a high degree of variability, with cross-resistance arising in at least one resistant sub-line for each drug. The most effective drug at overcoming acquired resistance was cabozantinib, with 3 out of 6 resistant sub-lines showing significantly decreased IC50 when treated with the drug compared to the parental cells.

Item Type: Thesis (Master of Science by Research (MScRes))
Thesis advisor: Michaelis, Martin
Thesis advisor: Wass, Mark
Uncontrolled keywords: Cancer biology, cancer drug resistance
Subjects: Q Science
Divisions: Faculties > Sciences > School of Biosciences
SWORD Depositor: System Moodle
Depositing User: System Moodle
Date Deposited: 19 Mar 2020 11:10 UTC
Last Modified: 23 Mar 2020 10:45 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/80550 (The current URI for this page, for reference purposes)
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