Shin, Hyungkyung Hwang, SuA Jeong, Jeong Hyun Shin, Sang Chul Oh, Yeonji Kim, Jinhyeok Hwang, Inah Kim, Eunice EunKyeong Choo, Hyunah Song, Eun Joo 2025-04-16T08:00:24Z 2025-04-16T08:00:24Z 2025-04-15 2025-05 1043-6618 https://pubs.kist.re.kr/handle/201004/152267 FDA-approved KRASG12C 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 KRASG12C-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 KRASG12C-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 KRASG12C-mutated NSCLC and introduce K-552 as a USP47 inhibitor with potential for combination therapy with KRASG12C inhibitors. English Academic Press Targeting USP47 enhances the efficacy of KRAS inhibitor in KRASG12C mutated non-small cell lung cancer by controlling deubiquitination of c-Myc Article 10.1016/j.phrs.2025.107722 1 Pharmacological Research, v.215 Pharmacological Research 215 Y scie scopus 001463914900001 Pharmacology & Pharmacy Pharmacology & Pharmacy Article NSCLC USP47 C-Myc KRAS Sotorasib