Dual inhibition of SUMOylation and MEK conquers MYC-expressing KRAS-mutant cancers by accumulating DNA damage

作者：Hiroshi Kotani, Hiroko Oshima, Justin C. Boucher, Tomoyoshi Yamano, Hiroyuki Sakaguchi, Shigeki Sato, Koji Fukuda, Akihiro Nishiyama, Kaname Yamashita, Koushiro Ohtsubo, Shinji Takeuchi, Takumi Nishiuchi, Masanobu Oshima, Marco L. Davila, Seiji Yano · 发表于：Journal of Biomedical Science · 年份：2024 · DOI：10.1186/s12929-024-01060-3 · 被引用次数：25 · 研究领域：Ubiquitin and proteasome pathways、Endoplasmic Reticulum Stress and Disease、Heat shock proteins research

BACKGROUND: inhibitors have recently been approved, effective precision therapies have not yet been established for all KRAS-mutant cancers. Many treatments for KRAS-mutant cancers, including epigenome-targeted drugs, are currently under investigation. Small ubiquitin-like modifier (SUMO) proteins are a family of small proteins covalently attached to and detached from other proteins in cells via the processes called SUMOylation and de-SUMOylation. We assessed whether SUMOylation inhibition was effective in KRAS-mutant cancer cells. METHODS: The efficacy of the first-in-class SUMO-activating enzyme E inhibitor TAK-981 (subasumstat) was assessed in multiple human and mouse KRAS-mutated cancer cell lines. A gene expression assay using a TaqMan array was used to identify biomarkers of TAK-981 efficacy. The biological roles of SUMOylation inhibition and subsequent regulatory mechanisms were investigated using immunoblot analysis, immunofluorescence assays, and mouse models. RESULTS: We discovered that TAK-981 downregulated the expression of the currently undruggable MYC and effectively suppressed the growth of MYC-expressing KRAS-mutant cancers across different tissue types. Moreover, TAK-981-resistant cells were sensitized to SUMOylation inhibition via MYC-overexpression. TAK-981 induced proteasomal degradation of MYC by altering the balance between SUMOylation and ubiquitination and promoting the binding of MYC and Fbxw7, a key factor in the ubiquitin-proteasome system. The effi...