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

  • J Clin Invest. 2025 Mar 17;135(6):e185278. doi: 10.1172/JCI185278.
Shihui Shen  1  2 ,  Qiansen Zhang  1 ,  Yuhan Wang  1 ,  Hui Chen  2 ,  Shuangming Gong  1 ,  Yun Liu  1 ,  Conghao Gai  3 ,  Hansen Chen  1 ,  Enhao Zhu  1 ,  Bo Yang  1 ,  Lin Liu  1 ,  Siyuan Cao  1 ,  Mengting Zhao  1 ,  Wenjie Ren  1 ,  Mengjuan Li  1 ,  Zhuoya Peng  1 ,  Lu Zhang  1 ,  Shaoying Zhang  1 ,  Juwen Shen  1 ,  Bianhong Zhang  1 ,  Patrick Kh Lee  4 ,  Kun Li  5 ,  Lei Li  2 ,  Huaiyu Yang  1
Affiliations
  • 1. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
  • 2. Joint Center for Translational Medicine, Shanghai Fifth People's Hospital, Fudan University and School of Life Science, East China Normal University, Shanghai, China.
  • 3. Organic Chemistry Group, College of Pharmacy, Naval Medical University, Shanghai, China.
  • 4. School of Energy and Environment, City University of Hong Kong, Hong Kong SAR, China.
  • 5. Health Science Center, East China Normal University, Shanghai, China.
PMID: 40091835 DOI: 10.1172/JCI185278
Abstract

Despite advances in the development of direct KRAS inhibitors, KRAS-mutant cancers continue to exhibit resistance to the currently available therapies. Here, we identified REGγ as a mutant KRAS-associated factor that enhanced REGγ transcription through the KRAS intermediate NRF2, suggesting that the REGγ-proteasome is a potential target for pan-KRAS inhibitor development. We elucidated a mechanism involving the KRAS/NRF2/REGγ regulatory axis, which links activated KRAS to the ATP- and ubiquitin-independent Proteasome. We subsequently developed RLY01, a REGγ-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 REGγ-proteasome by increasing REGγ expression, highlighting the potential of ubiquitin-independent Proteasome inhibition as a therapeutic approach for pan-KRAS-mutant cancers.

Keywords
Cancer; Drug therapy; Oncology; Therapeutics; Tumor suppressors.
Products