The New England Journal of MedicineSotorasib for Vascular Malformations Associated with KRAS G12C Mutation

KRAS G12C Inhibition: A Potential Breakthrough in Treating Vascular Malformations

A recent study demonstrates the efficacy of sotorasib, a KRAS G12C inhibitor, in treating vascular malformations associated with the KRAS G12C mutation. The research combines preclinical mouse models and clinical observations from two patients, offering new insights into the treatment of these challenging conditions.

Key Points:

• KRAS gain-of-function mutations are frequently observed in sporadic arteriovenous malformations, particularly in brain vasculature.
• Two mouse models were developed to study KRAS G12C-driven vascular malformations: KrasG12C-Cdh5 and KrasG12C-CAGG.
• Sotorasib, a small-molecule inhibitor that selectively targets KRAS G12C, was tested in both mouse models.
• In the KrasG12C-Cdh5 model, sotorasib reduced the occurrence of vascular malformations in the brain, lung, and spleen.
• Sotorasib treatment dampened AKT-mTOR and ERK pathway activation in both mutant and surrounding cells.
• In the more severe KrasG12C-CAGG model, sotorasib prevented early mortality and the development of vascular malformations.
• Two patients with severe KRAS G12C-related arteriovenous malformations were treated with sotorasib.
• Patient 1, a 24-year-old man, experienced reduced pain, cessation of bleeding, and decreased fatigue within 4 weeks of treatment.
• MRI showed a 31.5% reduction in vascular malformation volume after 24 months of treatment in Patient 1.
• The KRAS G12C mutation became undetectable in Patient 1’s plasma cell-free DNA by month 6 of treatment.
• Patient 2, a 45-year-old woman, experienced rapid clinical improvement, including deafness correction and pain reduction.
• Imaging at 6 months showed a 19.8% reduction in vascular infiltration for Patient 2.
• No significant drug-related adverse events were reported in either patient during treatment.
• The study highlights the importance of genetic testing in vascular malformations to guide targeted therapy.

Activating KRAS gene point mutations have been detected in many types of human tumors. Such oncogenic forms of the KRAS gene are prevalent in pancreatic carcinomas (>80%), colon carcinomas (40–50%), and lung carcinomas (30–50%), but are also present in biliary tract malignancies, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia, and breast cancer. (Journal of Biomedicine and Biotechnology)

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