Recently, researchers have developed a new approach to block the KRAS oncogene, one of the most frequently mutated genes in human cancer. The approach relies upon siRNA to attack KRAS, which is tantalizing yet elusive target for drug developers.
The findings, published in the journal Molecular Cancer Therapeutics, show that using a form of siRNA to halt KRAS not only dramatically stunted the growth of lung and colon cancers in cultured cells and mice but also blocked metastasis.
As known in the biomedical circle, KRAS is a signaling molecule — a protein switch that triggers a cascade of molecular events that tell cells to grow and survive. Mutations in the KRAS gene create a switch that is perpetually “on,” causing cells to divide uncontrollably. KRAS mutations are present in approximately 30% of human cancers, particularly lung, colon, pancreatic, and thyroid cancer.
Over the past decades, KRAS has been widely regarded as undruggable target, since it lacks good pockets or binding sites for small molecules and drug to bind to. Some researchers have tried instead to target the proteins downstream in the KRAS signaling cascade, but those attempts have also had limited success.
Instead of other conventional methods, a new genetic tool known as RNA interference (also called RNAi) is employed to destroy the KRAS protein before it fully forms. RNAi uses bits of synthetically engineered RNA to silence specific genes. These bits of RNA bind to specific genetic messages called mRNA in the cell and direct enzymes to recognize the messages as enemies. In this context, the enzymes destroyed the genetic messages of KRAS mRNA so that KRAS can’t be made. As a result, the cells don’t grow, replicate, or move nearly as well.
RNAi has shown great promise in the treatment of liver diseases, viral infections, and cancers. To see if this approach could thwart the KRAS oncogene, researchers had to test different sequences of RNA to determine which one most effectively tagged KRAS for destruction. Of five RNA sequences, the researchers identified two candidates worthy to take into cancer models.
When they delivered these sequences into tissue culture cells, they found that the siRNAs destroyed over 90% of the KRAS gene messages, significantly impairing the growth of cancer cell lines. The siRNA sequences will have to be designed to specifically target the mutant form of KRAS without disrupting the normal form of the gene, which is necessary for maintaining normal growth in healthy cells.
Therapeutic Silencing of KRAS using Systemically Delivered siRNAs. Molecular Cancer Therapeutics, 2014