Treating Cancers with KRAS Mutations by Attacking Secondary Genes

To overcome drug resistance in the more than 30% of cancers linked to mutations in the KRAS gene, cancer researchers have developed a method for targeting secondary genes that are required for the survival of the cancer cell.

KRAS (V-Ki-ras2; Kirsten rat sarcoma viral oncogene homologue) is the protein encoded by the KRAS gene. Like other members of the Ras family, the KRAS protein is a GTPase and is an early player in many signal transduction pathways. KRAS is usually anchored to cell membranes via an isoprenyl group on its C-terminus. While KRAS performs an essential function in normal tissue signaling, mutated KRAS genes are potent oncogenes that play a role in many types of cancer.

Investigators from Harvard Medical School (Cambridge, MA, USA) used advanced RNA interference techniques to differentiate between genes active in cancers caused by KRAS mutations and those active in cancers with normal KRAS genes. Results published in two articles in the May 29, 2009, issue of the journal Cell pointed to two potential drug targets.

One potential target gene is PLK-1 (polo-like kinase 1), which is a member of the serine/threonine protein kinase family, cdc5/polo subfamily. Highly homologous to polo-like kinase (Drosophila), PLK-1 contains two polo box domains with a predicted molecular weight of 68 kDa. This nuclear protein is highly expressed in the placenta and colon, and has been shown to regulate cdc2/cyclin B through phosphorylation and activation of cdc25c phosphatase. PLK-1 may also be required for cell division, while depletion of PLK-1 results in apoptosis.

The second target is the serine/threonine kinase STK33. The investigators found that cells that were dependent on mutant KRAS exhibited sensitivity to suppression of STK33 irrespective of tissue origin, whereas KRAS-independent cells did not require STK33. STK33 promoted cancer cell viability in a kinase activity-dependent manner by regulating the suppression of mitochondrial apoptosis.

"Cancer cells are not super cells,” said senior author Dr. Stephen J. Elledge, professor of genetics at Harvard Medical School. "They are very sick cells that have needed to make a lot of compromises. The modus operandi is to find the gene involved and to use that to try and ‘cure cancer' in some way. That has not always worked out because those mutations are not necessarily the best targets. This strategy allows us to ask what the best targets are, with no preconceived notions.”

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