Researchers have found an intriguing new function of RAS genes, known for their common mutations in cancer. Beyond their established role in signaling at the surface of cells, mutant RAS appears to initiate a chain reaction that facilitates the transport of certain nuclear proteins, leading to rampant tumor growth, as detailed in a recent study published on November 11, 2024, in *Nature Cancer*.
Researchers at the National Institutes of Health (NIH) and their collaborators have discovered a new way in which RAS genes, frequently mutated in cancer, may influence tumor growth beyond their established role in signaling at the cell surface. Mutant RAS, according to a study published on November 11, 2024, in Nature Cancer, initiates a series of events regarding the transport of specific nuclear proteins that ultimately lead to uncontrolled tumor growth.
RAS genes rank as the second most frequently mutated in cancer, with mutant RAS proteins significantly contributing to several of the deadliest cancer types, including nearly all cases of pancreatic cancer, around 50% of colorectal cancers, and one-third of lung cancers. Extensive research over the years has demonstrated that mutant RAS proteins advance tumor development and growth by activating particular proteins at the cell surface, triggering a continuous signal for cells to proliferate.
“This study is the first to demonstrate that mutated RAS genes can drive cancer in a completely novel manner,” remarked Douglas Lowy, M.D., the deputy director of NIH’s National Cancer Institute (NCI) and one of the study’s authors. “Uncovering this additional role of RAS proteins opens up exciting possibilities for enhancing treatment strategies.”
For only a few years, drugs that inhibit mutant RAS proteins have been available as cancer therapies and have gained approval from the Food and Drug Administration (FDA) for treating lung cancer and sarcoma. Despite their approval being hailed as a major triumph in science, RAS inhibitors have had a limited effect on patient outcomes, extending survival by only a few months for most individuals.
Over three decades ago, Dr. Lowy was part of a research group that clarified the role of RAS as a cancer-causing gene and detailed how it supports tumor growth. In the current study, the team discovered that mutant RAS directly participates in releasing a nuclear protein known as EZH2 from a complex being transported from the nucleus to the cytoplasm. Upon release, EZH2 promotes the degradation of a tumor suppressor protein named DLC1. When researchers blocked mutant RAS, it prevented the release of EZH2, leading to the reinstatement of DLC1’s function.
Through experiments using human lung cancer cell lines and mouse models, the researchers observed that using RAS inhibitors alongside various targeted drugs that reactivate DLC1’s tumor suppressor ability had a far greater impact on cancer than RAS inhibitors alone.
Additionally, the study provided indications that mutant RAS proteins carry out this function across other types of cancer, hinting at a broader mechanism that could apply to cancers with mutated RAS genes.
The researchers are optimistic about their findings and see potential for new treatment strategies for cancers driven by RAS mutations. They are currently exploring how this mechanism operates in pancreatic cancer, where effective treatment options remain scarce.
“It may be possible to develop new treatment combinations in the future that take into account this newly identified role of RAS,” Dr. Lowy concluded.
