For the most part, cancer therapy has been aimed at exploiting pathways that are present in cancer cells and not in normal cells but two studies published in the May 29th issue of the journal Cell suggest potential for an alternative approach. Blocking the activity of oncogenic protein kinases – either with antibodies or small molecules – has become an important field of interest in cancer research but, despite the prevalence of RAS mutations in human tumours, inhibition of oncogenic RAS has not been realised as a therapeutic strategy. As an alternative to directly targeting RAS, US researchers have now identified ‘normal’ genes that are needed for cell survival in the presence of mutant, but not wild-type, KRAS.
To identify genes that are essential for survival only in the context of mutant KRAS, the researchers used a short hairpin RNA (shRNA) library to carry out high-throughput loss-of-function RNA interference (RNAi) screens in cancer cell lines as well as in normal cells. Dozens of potential drug targets were identified including serine/threonine kinase 33 (STK33) and mitotic polo-like kinase 1 (PLK1).
Patients with KRAS tumours are more likely to survive if they also have reduced expression of genes in the PLK1 pathway, suggesting that PLK1 inhibitors may have the potential to prolong survival. Although not required by normal cells, STK33 was found to be essential for the survival of cancer cells, irrespective of their tissue of origin, again suggesting therapeutic potential for inhibitors.
As well as identifying new targets for which it may be possible to develop therapeutically useful inhibitors, the two studies demonstrate the potential of RNAi screens to discover functional dependencies between oncogenes and normal genes in cancer cells. Targeting proteins which are essential for the survival of cancer cells, but not normal cells, could lead to a substantial therapeutic window, especially if only partial knock-down is needed to kill cancer cells.