Metabolic Vulnerabilities Associated to G12C Inhibitor Resistance
Abstract
Acquired drug resistance to specific KRAS G12C inhibitors sotorasib and adagrasib has been already been detected in patients and thus alternative drug treatment approaches are needed. In this project we have seen a strong correlation between drug resistance and NNMT overexpression. Innate sensitive cell lines and PDOs have higher NNMT levels and genetic knock-out of this protein modulates drug sensitivity. Similarly, the acquisition of drug resistance to either sotorasib or adagrasib in sensitive models has shown a relevant increase in NNMT expression. These models of acquired drug resistance mimic what happens in the clinic when tumors are no longer sensitive to the treatment and the tumor relapses. Genetic repression of NNMT in acquired resistant models also affects drug sensitivity, recapitulating what happens in innate resistant models. NNMT is a metabolic enzyme that transfers methyl groups from universal donor SAM to nicotinamide, forming 1-MNA as a by-product. We have detected by UPLC-MS/MS that 1-MNA levels are higher in those models with higher levels of NNMT and significantly lower when NNMT protein is not detected. Finally, we have detected that those models with higher NNMT levels are more sensitive to NAMPT inhibition with daporinad.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2023
- Accession Number
- AD1207386
Entities
People
- Ines P. Endrino
Organizations
- University of Illinois Urbana–Champaign