RAS genes are the second most commonly mutated genes in cancer. Mutant RAS proteins drive the progression of some of the deadliest cancers, including nearly all pancreatic cancers, half of colorectal cancers, and one-third of lung cancers. These mutant proteins promote tumor growth by activating cell surface proteins, creating continuous growth signals that encourage uncontrolled cell division.
Researchers at the NIH have uncovered a new way mutant RAS genes contribute to cancer beyond their known role in surface signaling. This process leads to uncontrolled tumor growth, offering new insights into how RAS mutations promote cancer progression.
Study author Douglas Lowy, M.D., deputy director of NIH’s National Cancer Institute (NCI), said, “This is the first study to show that mutated RAS genes can promote cancer in an entirely new way. The finding of the additional role for RAS proteins has exciting implications for improving treatment.”
Drugs that block mutant RAS proteins have been available for cancer treatment in recent years, with FDA approval for use in lung cancer and sarcoma. However, these drugs have shown limited impact on patient outcomes, typically improving survival by only a few months.
A new study led by Dr. Lowy’s team has uncovered a novel mechanism by which mutant RAS contributes to cancer. The research reveals that mutant RAS releases the nuclear protein EZH2, promoting the breakdown of the tumor suppressor protein DLC1.
Blocking mutant RAS prevents EZH2 release, restoring DLC1 activity. In lung cancer cell lines and mouse model experiments, combining RAS inhibitors with drugs that reactivate DLC1 proved more effective in combating cancer than RAS inhibitors alone.
The study also found that mutant RAS proteins may perform this same function in other types of cancer, suggesting that the mechanism could be shared across cancers with mutated RAS genes. The researchers believe their discovery could lead to new treatment strategies for RAS-driven cancers. They are now focusing on how this RAS function affects pancreatic cancer, a type with few effective treatment options.
Journal Reference:
- Tripathi, B.K., Hirsh, N.H., Qian, X. et al. The pro-oncogenic noncanonical activity of a RAS•GTP:RanGAP1 complex facilitates nuclear protein export. Nat Cancer (2024). DOI: 10.1038/s43018-024-00847-5
