Skip to main content

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,. (KAR id:80550)

PDF
Language: English
Download this file
(PDF/1MB)
[thumbnail of 173Timo_Kuerten_MSc_Thesis_FINAL_Draft_WITH_CORRECTIONS.pdf]

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: Divisions > Division of Natural Sciences > Biosciences
Funders: Organisations -1 not found.
SWORD Depositor: System Moodle
Depositing User: System Moodle
Date Deposited: 19 Mar 2020 11:10 UTC
Last Modified: 01 Sep 2022 23:00 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/80550 (The current URI for this page, for reference purposes)

University of Kent Author Information

Kuerten, Timo Leopold.

Creator's ORCID:
CReDIT Contributor Roles:
  • Depositors only (login required):

Total unique views for this document in KAR since July 2020. For more details click on the image.