A team of researchers from the University of Toronto have discovered a mechanism to inhibit the cancer-causing activity of the protein most often responsible for the formation of tumors. Known as Ras, this protein serves to facilitate communication between cells by delivering signals from growth factor receptors on the outside of the cell to the DNA-containing nucleus. However, when these proteins become overactive, the messages they carry can become distorted, sometimes resulting in uncontrolled proliferation of cells and the subsequent development of tumors.
Though the role of Ras in cancer has long been known about, researchers had until now failed to identify a way to prevent it from becoming overactive, resulting in its reputation as an “undruggable” process. However, the researchers behind a new study – which appeared in Nature Communications – now appear to have done so, by inhibiting another protein called SHP2.
Under normal conditions, Ras is deactivated once it becomes phosphorylated – a process which involves the binding of a phosphate group to the protein. As such, its activity is kept under control and the signals it carries are regulated. However, SHP2 reactivates Ras by stimulating its dephosphorylation, i.e. the removal of the phosphate group. This causes it to become hyperactive and deliver distorted messages to the cell nucleus, inappropriately stimulating cell division.
In mice prone to an aggressive form of brain tumor called glioblastoma, it was discovered that SHP2 levels were heightened in the type of brain cells that become cancerous. By using a specific pharmacological agent to inhibit SHP2 in mice that had gone on to develop this type of cancer, researchers noted a “very significant decrease” in tumor size, resulting in a similarly large rise in survival rates. Commenting on this data, study co-author Michael Ohh said in a statement that “the inhibitors’ results were incredible – we were shocked,” adding that “nothing has had the same effect.”
Based on the evidence obtained from their experiments with mice, the researchers conclude that “it is therefore plausible that targeting Ras signalling via the inhibition of SHP2 would attenuate the growth of gliomas [a type of malignant tumor] in humans.” However, the research remains at an early stage, and more work is needed before this information can be used to create new cancer therapies. The researchers hope that their discovery will kick-start this process, and potentially lead to clinical trials in humans in the near future.
