KRAS inhibitor shrinks NF1 nerve tumors in mice

Twice a day, mice carrying NF1 nerve tumors received an oral dose of BI6674. In the model developed by Nancy Ratner's team at Cincinnati Children's, the KRAS inhibitor reduced neurofibroma burden by at least as much as FDA-approved MEK inhibitors—a preclinical result published in Science Advances in 2026.

NF1 causes Schwann cell tumors called neurofibromas to grow within peripheral nerves. It affects about one in every 2,500 to 3,000 newborns, while about 100,000 to 120,000 people of all ages live with an NF diagnosis in the United States. Most people have mild symptoms and live a normal lifespan, but tumors in the brain, nerve tumors that block airways, or tumors in other critical locations can cause severe risks. About 8% to 13% of patients develop malignant peripheral nerve sheath tumors, and about 250 people a year in the United States die from NF1.

The researchers used genetically engineered Dhh-Cre;Nf1 fl/fl mice to test the idea that KRAS is a vulnerability in established tumors. KRAS normally acts like an on-off switch for nerve growth; when Schwann cells lack Nf1, the protein plays a dominant role in tumor formation. BI6674 blocked KRAS, reduced the tumor burden and changed immune-cell behavior in the tumor microenvironment. That result matters because MEK inhibitors, including selumetinib and mirdametinib, have helped many patients but leave about 30% with no response, while tumor shrinkage is rarely greater than 20% and ongoing treatment can bring dose-limiting toxicities.

The mouse study also found no hypertrophy, hyperplasia or tumor formation in the nerve roots, dorsal root ganglia and peripheral nerves examined after treatment—not even in old mice aged 25–30 months. Because KRAS inhibitors act at a different point in the disease pathway, they may cause fewer severe side effects than MEK inhibitors, but that remains to be tested in people. The drugs could become an alternative for patients who tolerate MEK inhibitors poorly, or potentially be combined with them.

For patients and families, the near-term consequence is a stronger research option, not a new treatment yet. Human clinical trials must determine the right dosing schedule, especially for growing children, and show whether benefits last as long in people as they did in mice. BI6674 may not be the only or best KRAS inhibitor for human use, so Ratner's team plans to test other compounds as well.