Mouse study models lung tumors escaping KRAS inhibition
MIT researchers found that changing tumor type can provide another route to resistance, while possible alternative growth pathways remain under investigation.
AI illustrationMIT researchers used an engineered mouse lung cancer model to study how tumors can resist KRAS-inhibiting treatment by changing their type. The work examines a route distinct from resistance that restores or increases KRAS activity.
Anne Trafton reported the findings in MIT News. The study appeared in Nature Genetics, with Carrie Rodriguez and Nicolas Mathey-Andrews as lead authors and Tyler Jacks as senior author.
In the model, researchers introduced the mutation targeted by approved KRAS inhibitors. After treatment with a KRAS-G12C inhibitor, tumors lacking the gene Nkx2-1 could change from adenocarcinoma to squamous cell carcinoma. Nkx2-1 normally helps cells retain their alveolar epithelial identity.
Activating DeltaNp63, a factor involved in controlling gene activity, also increased the likelihood of this change. Another factor, SOX2, helped the process but could not start it alone.
The transformed tumors did not develop the changes that typically increase KRAS expression in adenocarcinomas. Instead, their KRAS signaling was shut down. Researchers hypothesize that another signaling pathway may allow these cells to keep growing; identifying it remains part of their ongoing work.
The study follows an earlier observation in patients. A 2021 investigation at Dana-Farber Cancer Institute examined tumors from 17 people treated with KRAS-G12C inhibition. In two patients, tumors changed type without obvious resistance mutations, according to the report.
The new research models factors that might drive that transition rather than demonstrating a new treatment for patients. Researchers are now examining cells as they enter the squamous state, hoping to find weaknesses that could be targeted by future drugs.
The findings underline that resistance can follow different routes. Discovering possible drug targets remains an aim of the research, and the alternative signals supporting the transformed cells have not yet been identified in this report.