Targeting USP47 enhances the efficacy of KRAS inhibitor in KRAS^G12C mutated non-small cell lung cancer by controlling deubiquitination of c-Myc

FDA-approved KRAS^G12C inhibitors, like Sotorasib, target G12C-mutated KRAS in NSCLC. However, issues with insensitivity and drug resistance have emerged, requiring the development of new combination therapies to overcome these limitations. USP47 has been identified as a regulator of cancer-related signaling pathways such as Wnt, Hippo, and p53. However, its role in the KRAS signaling pathway remains largely unexplored and USP47 inhibitors are less developed than those targeting its homolog, USP7. Here, we identify USP47 as a novel therapeutic target in KRAS^G12C-mutated NSCLC and report K-552, a selective USP47 inhibitor, as a potential treatment strategy. We demonstrate that USP47 stabilizes c-Myc by preventing its proteasomal degradation through deubiquitination, thereby promoting NSCLC cell proliferation. Additionally, the compound K-552, a USP47 inhibitor identified through virtual screening, effectively destabilizes c-Myc and inhibits KRAS^G12C-mutated NSCLC cell proliferation. Furthermore, USP47 inhibition—either by siRNA knockdown or K-552 treatment—enhances the efficacy of Sotorasib in vitro and in vivo. Together, our findings establish USP47 as a promising therapeutic target in KRAS^G12C-mutated NSCLC and introduce K-552 as a USP47 inhibitor with potential for combination therapy with KRAS^G12C inhibitors.