Use this URL to cite or link to this record in EThOS:
Title: Probing RAS signalling : an activated oncogene 'synthetic lethal' screen
Author: Steckel, M.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2010
Availability of Full Text:
Access from EThOS:
Full text unavailable from EThOS. Please try the link below.
Access from Institution:
Anti-cancer drugs often affect both cancer and normal cells resulting in undesirable side effects. The concept of synthetic lethality offers a way to discover drug targets circumventing this problem. Genes which are synthetic lethal to a specific oncogenic lesion may provide novel targets for preferential killing of cancer cells. I have employed large-scale siRNA screening to identify genes that are synthetic lethal in the background of oncogenically activated RAS, which is found in approximately 30% of all human cancers. An isogenic pair of commonly used colon cancer cell lines, one bearing an activating KRAS mutation, the other with the mutated allele being removed by homologous recombination, were screened for loss of viability and apoptosis induction. Genes that preferentially induce cell death in the oncogenic cell line were identified by differential Z-Score analysis. Hits were validated and filtered by deconvolution of siRNA pools and by screening in a second isogenic cell line. Top hits were further screened in a larger panel of cancer cell lines with or without KRAS mutation. In addition, several drug classes were identified to preferentially induce cell death in KRAS mutant cell lines and combination of these drugs showed enhanced apoptosis induction in the background of activated KRAS. Further evaluation of the identified hits should reveal important cancer drug targets in the context of oncogenic RAS, as well as further insight into RAS signalling in general.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available