Does inappropriate DNA replication provide a mechanism for the de novo acquisition of drug resistance?
type: CreativeWork
description: EGFR is the most common driver mutation in non-small cell lung cancer (NSCLC) and is a common drug target across several cancers. Targeted therapeutics such as those that target EGFR (e.g. Osimertinib) have brought significant patient benefit, however ultimately patients tumours develop resistance to targeted treatments. Initial tumour response followed by a period of dormancy before progressing in patients treated by targeted therapies has been modelled in vitro through the drug tolerant persister (DTP) phenotype system. It Is vitally important that the underlying mechanisms by which cancer DTP cells gain resistance mutations/mechanisms to targeted treatments is better understood to aid the further development of therapeutics and the directed design of highly effective combination treatments. This work initially investigates the ability of DTP cells to undergo DNA replication across multiple in vitro NSCLC DTP model systems. Interestingly, all DTP cells were able to undergo DNA replication rather than a specific subpopulation, and a large proportion of DTP cells are undergoing DNA replication at a given time. This ability of DTP cells to undergo DNA replication under targeted treatment appears to be necessary for the survival of the DTP culture. Through collaboration with AstraZeneca, I then investigated the effect of several combination therapies on the cell number, replicative fraction, and DNA damage repair (DDR) markers in multiple in vitro NSCLC DTP model systems. Osimertinib treatment led to the emergence of a subset of cells with a high DDR marker burden, which was further heightened when combined with PARP inhibitors. Notably, combining Osimertinib with either Palbociclib (a CDK4/6 inhibitor) or AZD1390 (an ATM inhibitor) enhanced cell killing beyond single-agent Osimertinib, with only the Palbociclib combination reducing the replicative fraction of DTP cells. I then explored the fate of DTP cells. Interestingly, although they complete the cell cycle prolon…
abstract: EGFR is the most common driver mutation in non-small cell lung cancer (NSCLC) and is a common drug target across several cancers. Targeted therapeutics such as those that target EGFR (e.g. Osimertinib) have brought significant patient benefit, however ultimately patients tumours develop resistance to targeted treatments. Initial tumour response followed by a period of dormancy before progressing in patients treated by targeted therapies has been modelled in vitro through the drug tolerant persister (DTP) phenotype system. It Is vitally important that the underlying mechanisms by which cancer DTP cells gain resistance mutations/mechanisms to targeted treatments is better understood to aid the further development of therapeutics and the directed design of highly effective combination treatments. This work initially investigates the ability of DTP cells to undergo DNA replication across multiple in vitro NSCLC DTP model systems. Interestingly, all DTP cells were able to undergo DNA replication rather than a specific subpopulation, and a large proportion of DTP cells are undergoing DNA replication at a given time. This ability of DTP cells to undergo DNA replication under targeted treatment appears to be necessary for the survival of the DTP culture. Through collaboration with AstraZeneca, I then investigated the effect of several combination therapies on the cell number, replicative fraction, and DNA damage repair (DDR) markers in multiple in vitro NSCLC DTP model systems. Osimertinib treatment led to the emergence of a subset of cells with a high DDR marker burden, which was further heightened when combined with PARP inhibitors. Notably, combining Osimertinib with either Palbociclib (a CDK4/6 inhibitor) or AZD1390 (an ATM inhibitor) enhanced cell killing beyond single-agent Osimertinib, with only the Palbociclib combination reducing the replicative fraction of DTP cells. I then explored the fate of DTP cells. Interestingly, although they complete the cell cycle prolon…
author: May, Kieron
language: eng
keywords: Oncology, DNA sequencing, DNA replication, DNA damage
license: https://www.repository.cam.ac.uk/bitstreams/40d40033-ba13-4454-a14a-7e1cbf428181/download
license: http://purl.org/NET/rdflicense/allrightsreserved
date published: 2025-09-26
date modified: 2026-07-22T22:24:13Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.124219