Comprehensive antitumor immune response boosted by dual inhibition of SUMOylation and MEK in MYC-expressing KRAS-mutant cancers

作者：Hiroshi Kotani, Tomoyoshi Yamano, Justin C. Boucher, Shigeki Sato, Hiroyuki Sakaguchi, Koji Fukuda, Akihiro Nishiyama, Kaname Yamashita, Koushiro Ohtsubo, Shinji Takeuchi, Takumi Nishiuchi, Hiroko Oshima, Masanobu Oshima, Marco L. Davila, Seiji Yano · 发表于：Experimental Hematology and Oncology · 年份：2024 · DOI：10.1186/s40164-024-00563-x · 被引用次数：9 · 研究领域：Ubiquitin and proteasome pathways、Histone Deacetylase Inhibitors Research、interferon and immune responses

Precision medicine has drastically changed cancer treatment strategies including KRAS-mutant cancers which have been undruggable for decades. While intrinsic or acquired treatment resistance remains unresolved in many cases, epigenome-targeted therapy may be an option to overcome. We recently discovered the effectiveness of blocking small ubiquitin-like modifier (SUMO) signaling cascade (SUMOylation) in MYC-expressing KRAS-mutant cancer cells using a SUMO-activating enzyme E inhibitor TAK-981 that results in SUMOylation inhibition. Interestingly, TAK-981 promoted the degradation of MYC via the ubiquitin-proteasome system. Moreover, combination therapy with TAK-981 and MEK inhibitor trametinib remarkably regressed xenografted KRAS-mutant tumors by accumulating DNA damage and inducing apoptosis. Whereas our recent study revealed immune-independent antitumor efficacy, we evaluated the immune responses of cancer cells and immune cells in this study. We found that TAK-981-induced MYC downregulation promoted the activation of STING followed by Stat1 and MHC class I in KRAS-mutant cancer cells. Activation of dendritic cells or T cells treated with TAK-981 was also verified by upregulated activation markers in dendritic cells or skew-toward effector-like phenotypes in T cells. Furthermore, the enhanced immune-dependent antitumor efficacy of the combination therapy with TAK-981 and trametinib was confirmed by infiltration of immune cells into tumor tissues and immunodepleting-test usi...