The pro-oncogenic noncanonical activity of a RAS•GTP:RanGAP1 complex facilitates nuclear protein export

Tue Nov 12 10:24:30 UTC 2024: ## New Discovery: KRAS Uses Noncanonical Signaling Pathway to Promote Tumor Growth

**Bethesda, MD** – Researchers at the National Cancer Institute (NCI) have identified a previously unknown mechanism by which the KRAS protein, commonly mutated in cancers, promotes tumor growth. This mechanism, dubbed “noncanonical RAS signaling”, operates independently of the well-studied canonical pathways and utilizes a protein complex involving KRAS and the Ran GTPase-activating protein 1 (RanGAP1).

The study, published in *Nature Cancer*, reveals that the KRAS-RanGAP1 complex plays a crucial role in nuclear protein export, a process that moves proteins from the nucleus to the cytoplasm. The research team found that this noncanonical activity of KRAS is essential for the export of EZH2, a protein that contributes to the degradation of the DLC1 tumor suppressor protein.

“We were surprised to find that KRAS, known for its role in regulating cell growth and survival, also has a direct impact on nuclear protein export,” said Brajendra Tripathi, PhD, lead author of the study. “This discovery significantly expands our understanding of how RAS mutations drive cancer development.”

The study also demonstrates that inhibiting the KRAS-RanGAP1 complex, either through targeted KRAS inhibitors or through XPO1 inhibitors (which block protein export), can effectively reduce tumor growth in preclinical models. This finding suggests a promising new therapeutic approach for cancers driven by KRAS mutations.

Furthermore, the researchers found that combining KRAS inhibitors with drugs that reactivate the tumor suppressor activity of DLC1, such as SRC inhibitors and AKT inhibitors, could lead to even greater tumor suppression.

These findings have significant implications for understanding and treating cancers with KRAS mutations. The discovery of the noncanonical RAS signaling pathway highlights the complexity of KRAS function and suggests new therapeutic targets for developing more effective cancer treatments.