A study published in PNAS shows how pancreatic cancer cells develop resistance to a targeted therapy in Pancreatic ductal adenocarcinoma.
Researchers focused on the KRAS inhibitor MRTX-1133, which initially blocks tumor growth by shutting down a key cancer-driving pathway. However, cancer cells quickly adapt by increasing levels of a protein called Fra-2. This triggers a switch in gene activity that boosts mTOR signaling, allowing the tumor to bypass KRAS inhibition and continue growing.
The study found this resistance pattern in cell lines, organoid models, and patient data, confirming a strong link between Fra-2 and mTOR activation. When Fra-2 was removed in experimental models, tumors became much more sensitive to treatment.
To counter this resistance, researchers tested a combination of MRTX-1133 with T-5224, a drug that blocks AP-1 activity. The combination prevented mTOR activation and significantly improved treatment response in preclinical models.
The findings suggest that targeting Fra-2-driven adaptation could help extend the effectiveness of KRAS-targeted therapies in pancreatic cancer.