Dr. Ladanyi Discusses Research on RRAS and RRAS2 Hotspot Mutations

Marc Ladanyi, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, joined Lung Cancers Today to discuss and share insights from his research on novel genetic oncogenic drivers in lung adenocarcinoma, which was presented at the 2025 European Lung Cancer Congress (ELCC).

The study evaluated genetic hotspot mutations in RRAS and RRAS2 for oncogenicity in lung adenocarcinoma. Although the genes “share sequence homology” with other genes in which mutations are well-known oncogenic drivers, similar mutations in RRAS and RRAS2 have not been as “well-characterized” in lung adenocarcinoma.

“Out of 7,291 patients with lung adenocarcinoma, we found 59 patients that had mutations in either RRAS or RRAS2,” Dr. Ladanyi said. “These mutations were typically mutually exclusive with other major lung cancer drivers like KRAS, EGFR, ALK fusion, and interestingly, they most commonly occurred in hotspots that corresponded to the KRAS Q61 mutational hotspot.”

When the mutational hotspots of RRAS Q67 and RRAS2 Q72 were aligned with the known oncogenic driver KRAS Q61, the results suggested that these hotspot mutations demonstrated effects on RRAS and RRAS2 similar to those shown in KRAS Q61, revealing their potential oncogenicity. These mutations also showed sensitivity to the  tumor-targeting pan-RAS inhibitor RMC-6236.

“We also put these mutants into human bronchiolar epithelial cells, HBECs, and showed that they induced growth in vivo and when xenografted into immunodeficient mice,” Dr. Ladanyi explained. “If you treat the mice with the pan-RAS inhibitor, you get in vivo arrested growth of these HBECs.”

In reflecting on the findings, Dr. Ladanyi emphasized that the results suggest RRAS and RRAS2 hotspot mutations have the capacity to act as oncogenic drivers in a small subset (0.5%) of patients with lung adenocarcinoma. The next step in continuing his research is to further expand the study data to identify other recurrent mutations with the potential for oncogenicity.

“One of the things we’re interested in is looking at additional genes that are involved in RAS signaling—either in a positive way or negative way—that have not been screened in large numbers to see if there are some recurrent hotspot mutations in such genes,” he explained. “RAS signaling is very complex. There are many members, and it’s possibly that the other members that have not been extensively studied may have mutations. And if those mutations are at the 0.5% level, they will not be recognized in smaller studies. You need large numbers.”