One of the most commonly mutated genes in human cancer, the KRAS oncogene, has been successfully blocked by a new method developed by researchers from The University of North Carolina School of Medicine (UNC; NC, USA) and The University of Texas MD Anderson Cancer Center (TX, USA). The findings, which were published recently in Molecular Cancer Therapeutics, present a potential new approach to inhibiting this ‘undruggable’ target.
Mutations in the KRAS gene occur in approximately 30% of human cancers and cause cells to grow and divide uncontrollably. Previously the targeting of KRAS has proven difficult for drug developers: “It is the elephant in the room,” commented lead researcher Chad Pecot (UNC School of Medicine). “KRAS was one of the first cancer-causing genes ever discovered, and it was the obvious target to go after. People have been trying for decades to hit it, but they haven’t had much luck.”
“KRAS has been widely regarded as an undruggable protein, but we show that that’s simply not the case,” commented Pecot. The new approach developed by Pecot and his team offers an alternative route to attack the KRAS oncogene, through use of RNA interference (RNAi) via small interfering RNAs (siRNAs).
RNAi utilizes parts of synthetically engineered RNA to silence defined genes. This RNA binds to mRNA within the cell and causes the cell enzymes to identify these as enemies. Consequently, in the case of targeting the KRAS gene, the KRAS mRNA messages would be destroyed and KRAS would no longer be produced, resulting in the prevention of effective cell growth or replication.
The team identified two specifically sequenced siRNAs that held the potential to effectively halt the functioning of KRAS and selected these for testing in cancer models. Their results suggested that the use of these siRNAs dramatically reduced the proliferation of colon and lung cancers in both cultured cells and mouse models. The new method also effectively prevented metastasis, the principal cause of cancer deaths.
Other attempts to inhibit KRAS signaling have been problematic as the protein lacks suitable positions for small molecules and drugs to bind to. Due to this, some research teams have attempted to target proteins downstream in the KRAS signaling cascade, but these have had limited success.
On delivery into cultured cells, the siRNAs destroyed > 90% of the KRAS gene messages and significantly inhibited the growth of cancer cell lines. In addition, the technique resulted in the reduction in expression of the signaling molecules pERK and pMEK, which are positioned downstream of KRAS and are also related to cancer cell proliferation and tumor growth.
The siRNAs were also wrapped in protective lipid nanoparticles and delivered in solution into mouse models of lung and colon cancer. This treatment notably reduced the growth of primary tumors and also halted the spread of cancer to other organs.
In colon cancer models, primary tumor growth was reduced by 69% after treatment with the siRNAs compared to control RNA sequences. Additionally, in both the colon and lung cancer mouse models secondary malignant growths were reduced by approximately 80%.
While promising, these results are only an initial step towards successfully combating the KRAS gene. siRNA sequences that do not disrupt the nonmutated gene functioning in addition to the mutant form are needed, added Pecot.