Volume 22, No 8, Aug 2012
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 22 Issue 8, August 2012: 1227-1245
ORIGINAL ARTICLES
Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies
Michael Steckel1,*, Miriam Molina-Arcas1,*, Britta Weigelt1, Michaela Marani1, Patricia H Warne1, Hanna Kuznetsov1, Gavin Kelly2, Becky Saunders3, Michael Howell<
1Signal Transduction, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK
2Bioinformatics and Biostatistics, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK
3High Throughput Screening Laboratories, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK
Correspondence: Julian Downward,(julian.downward@cancer.org.uk)
Oncogenic mutations in RAS genes are very common in human cancer, resulting in cells with well-characterized selective advantages, but also less well-understood vulnerabilities. We have carried out a large-scale loss-of-function screen to identify genes that are required by KRAS-transformed colon cancer cells, but not by derivatives lacking this oncogene. Top-scoring genes were then tested in a larger panel of KRAS mutant and wild-type cancer cells. Cancer cells expressing oncogenic KRAS were found to be highly dependent on the transcription factor GATA2 and the DNA replication initiation regulator CDC6. Extending this analysis using a collection of drugs with known targets, we found that cancer cells with mutant KRAS showed selective addiction to proteasome function, as well as synthetic lethality with topoisomerase inhibition. Combination targeting of these functions caused improved killing of KRAS mutant cells relative to wild-type cells. These observations suggest novel targets and new ways of combining existing therapies for optimal effect in RAS mutant cancers, which are traditionally seen as being highly refractory to therapy.
Cell Research (2012) 22:1227-1245. doi:10.1038/cr.2012.82; published online 22 May 2012
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