In a study reported on Sept. 30, 2026, MIT researchers modeled an alternative way lung tumors can escape KRAS-inhibiting drugs. About 25 percent of lung adenocarcinomas carry KRAS mutations, and the two FDA-approved KRAS inhibitors target the KRAS-G12C mutation, which they are approved to treat in patients whose tumors have not responded to other drugs. The inhibitors are effective in about 35 percent of patients who receive them, but tumors almost always develop resistance.

The team engineered a mouse lung cancer model carrying the targeted mutation. After treatment with a KRAS-G12C inhibitor, tumors with genetic loss of Nkx2-1 could undergo an adeno-to-squamous transition; activating DeltaNp63 or, secondarily, SOX2 made this more likely. These transformed tumors showed reduced KRAS signaling rather than the usual resistance mutations.

The authors, including lead authors Carrie Rodriguez and Nicolas Mathey-Andrews and senior author Tyler Jacks, published the work in Nature Genetics. They said further work may identify targets to prevent resistance.