Probing RAS signalling: an activated oncogene “synthetic lethal” screen

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