Targeting ubiquitin-independent proteasome with small molecule increases susceptibility in pan-KRAS–mutant cancer models
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.
Authors
- Bo Yang
- Patrick K. H. Lee (ORCID: https://orcid.org/0000-0003-0911-5317)
- Kun Li (ORCID: https://orcid.org/0000-0002-5863-9865)
- M J Li (ORCID: https://orcid.org/0000-0002-7278-1163)
- Yun Liu (ORCID: https://orcid.org/0000-0002-7745-1083)
- Zhanhui Peng (ORCID: https://orcid.org/0009-0002-0908-3781)
- Enhao Zhu
- Si-Yuan Cao (ORCID: https://orcid.org/0000-0001-5143-4501)
- Bianhong Zhang (ORCID: https://orcid.org/0000-0002-8669-2495)
- Shaoying Zhang (ORCID: https://orcid.org/0000-0002-0712-1687)
- Minghui Zhao (ORCID: https://orcid.org/0000-0001-8928-9258)
- Hansen Chen (ORCID: https://orcid.org/0000-0001-9506-6894)
- Shijing Gong (ORCID: https://orcid.org/0000-0002-9292-7609)
- Qiansen Zhang (ORCID: https://orcid.org/0000-0002-8608-3067)
- Conghao Gai (ORCID: https://orcid.org/0000-0001-6760-5045)
- Huaiyu Yang (ORCID: https://orcid.org/0000-0003-2358-1840)
- Hui Chen (ORCID: https://orcid.org/0000-0002-9785-4744)
- Yuhan Wang (ORCID: https://orcid.org/0009-0004-6281-0022)
- Lu Zhang (ORCID: https://orcid.org/0000-0002-0279-4751)
- Lei Li (ORCID: https://orcid.org/0000-0001-6990-1825)
- Lin Liu
- Shihui Shen
- Juwen Shen
- Wenjie Ren
Institutions
- City University of Hong Kong (HK)
- Fudan University (CN)
- East China Normal University (CN)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-03-16
- DOI
- https://doi.org/10.1172/jci185278
- Citations
- 1
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- National Natural Science Foundation of China