New Role for Mutant Proteins in Some Deadly Cancers Discovered

National Institutes of Health (NIH) scientists and collaborators say they have discovered a new way in which RAS genes, commonly mutated in cancer, may drive tumor growth beyond their well-known role in signaling at the cell surface.

Mutant RAS helps to initiate a series of events involving the transport of specific nuclear proteins that lead to uncontrolled tumor growth, according to the researchers’ study “The pro-oncogenic noncanonical activity of a RAS•GTP:RanGAP1 complex facilitates nuclear protein export” in Nature Cancer.

RAS genes are the second most frequently mutated genes in cancer, and mutant RAS proteins are key drivers of some of the deadliest cancers, including nearly all pancreatic cancers, half of colorectal cancers, and one-third of lung cancers. Decades of research have shown that mutant RAS proteins promote the development and growth of tumors by activating specific proteins at the cell surface, creating a constant stream of signals telling cells to grow.

“This is the first study to show that mutated RAS genes can promote cancer in an entirely new way,” said study author Douglas Lowy, MD, deputy director of NIH’s National Cancer Institute (NCI). “The finding of the additional role for RAS proteins has exciting implications for improving treatment.”

Applications for the treatment of RAS-fueled cancers

The researchers believe their work may have potential applications for the treatment of RAS-fueled cancers. They have started to look at how this function for RAS works in pancreatic cancer in particular because there are so few effective treatments for this type of cancer.

Drugs that block mutant RAS proteins have been available as cancer treatments for only a few years and have been approved by the FDA to treat lung cancer and sarcoma. Although their development was a major scientific success, RAS inhibitors have thus far had a limited impact on patient outcomes, improving survival by only a few months in most people.

Over 35 years ago, a group led by Lowy contributed to the early studies that identified RAS as a cancer-causing gene and helped explain how it promotes tumor growth. In this new study, the research team found that mutant RAS is directly involved in the process of releasing the nuclear protein EZH2 from a complex transported from the nucleus to the cytoplasm. Once released, EZH2 facilitates the breakdown of a tumor suppressor protein called DLC1. Blocking mutant RAS stopped EZH2 from being released, restoring the activity of DLC1.

In experiments in human lung cancer cell lines and mouse models of lung cancer, the researchers found that combining RAS inhibitors with different targeted cancer drugs that reactivate DLC1’s tumor suppressor activity had potent activity against cancer—more potent than that of RAS inhibitors alone.

The study also found evidence that mutant RAS proteins perform this same function in other cancer types, suggesting that this mechanism may be a general feature of cancers with mutated RAS genes.

“New treatment combinations could one day be developed that take this new role for RAS into consideration,” said Lowy.