Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade.
Douglas B FoxRichard Y EbrightXin HongHunter C RussellHongshan GuoThomas J LaSalleBen S WittnerNicolas PouxJoanna A VuilleMehmet TonerNir HacohenGenevieve Marie BolandDebattama R SenRyan J SullivanShyamala MaheswaranDaniel A HaberPublished in: NPJ precision oncology (2023)
Immune checkpoint blockade (ICB) has demonstrated efficacy in patients with melanoma, but many exhibit poor responses. Using single cell RNA sequencing of melanoma patient-derived circulating tumor cells (CTCs) and functional characterization using mouse melanoma models, we show that the KEAP1/NRF2 pathway modulates sensitivity to ICB, independently of tumorigenesis. The NRF2 negative regulator, KEAP1, shows intrinsic variation in expression, leading to tumor heterogeneity and subclonal resistance.