Targeting ubiquitin-independent proteasome with small molecule increases susceptibility in pan-KRAS mutant cancers

Despite advances in the development of direct KRAS inhibitors, KRAS-mutant cancers continue to exhibit resistance to the currently available therapies. Here, we identified REG? as a mutant KRAS-associated factor that enhances REG? transcription through the KRAS intermediate NRF2, suggesting that the REG?-proteasome is a potential target for pan-KRAS inhibitor development. We elucidated a novel mechanism involving the KRAS/NRF2/REG? regulatory axis, which links activated KRAS to the ATP- and ubiquitin-independent proteasome. We subsequently developed RLY01, a novel REG?-proteasome inhibitor that effectively suppressed tumor growth in KRAS-mutant cancer models and lung cancer organoids. Notably, the combination of RLY01 and the KRASG12C inhibitor AMG510 exhibited enhanced antitumor efficacy in KRASG12C cancer cells. Collectively, our data support the hypothesis that KRAS mutations enhance the capacity of the REG?-proteasome by increasing REG? expression, highlighting the potential of ubiquitin-independent proteasome inhibition as a therapeutic approach for pan-KRAS mutant cancers. Overall design: ChlP-seq of NRF2 in HCT116 cells, in triplicate,using Illumina GAllx.