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

Shihui Shen; Qiansen Zhang; Yuhan Wang; Hui Chen; Shuangming Gong; Yun Liu; Conghao Gai; Hansen Chen; Enhao Zhu; Bo Yang; Lin Liu; Siyuan Cao; Mengting Zhao; Wenjie Ren; Mengjuan Li; Zhuoya Peng; Lu Zhang; Shaoying Zhang; Juwen Shen; Bianhong Zhang; Patrick K.H. Lee; Kun Li; Lei Li; Huaiyu Yang

doi:10.1172/JCI185278

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

Shihui Shen
, Qiansen Zhang^*
, Yuhan Wang
, Hui Chen
, Shuangming Gong
, Yun Liu
, Conghao Gai
, Hansen Chen
, Enhao Zhu
, Bo Yang
, Lin Liu
, Siyuan Cao
, Mengting Zhao
, Wenjie Ren
, Mengjuan Li
, Zhuoya Peng
, Lu Zhang
, Shaoying Zhang
, Juwen Shen
, Bianhong Zhang

Patrick K.H. Lee, Kun Li^*, Lei Li^*, Huaiyu Yang^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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 panKRAS 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 KRAS^G12C inhibitor AMG510 exhibited enhanced antitumor efficacy in KRAS^G12C 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.

Original language	English
Article number	e185278
Journal	Journal of Clinical Investigation
Volume	135
Issue number	6
DOIs	https://doi.org/10.1172/JCI185278
State	Published - 17 Mar 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1172/JCI185278

Cite this

Shen, S., Zhang, Q., Wang, Y., Chen, H., Gong, S., Liu, Y., Gai, C., Chen, H., Zhu, E., Yang, B., Liu, L., Cao, S., Zhao, M., Ren, W., Li, M., Peng, Z., Zhang, L., Zhang, S., Shen, J., ... Yang, H. (2025). Targeting ubiquitin-independent proteasome with small molecule increases susceptibility in pan-KRAS–mutant cancer models. Journal of Clinical Investigation, 135(6), Article e185278. https://doi.org/10.1172/JCI185278

@article{3dc6e10716a541a9a2dfb9f2e56ec5c7,

title = "Targeting ubiquitin-independent proteasome with small molecule increases susceptibility in pan-KRAS–mutant cancer models",

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 panKRAS 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.",

author = "Shihui Shen and Qiansen Zhang and Yuhan Wang and Hui Chen and Shuangming Gong and Yun Liu and Conghao Gai and Hansen Chen and Enhao Zhu and Bo Yang and Lin Liu and Siyuan Cao and Mengting Zhao and Wenjie Ren and Mengjuan Li and Zhuoya Peng and Lu Zhang and Shaoying Zhang and Juwen Shen and Bianhong Zhang and Lee, \{Patrick K.H.\} and Kun Li and Lei Li and Huaiyu Yang",

note = "Publisher Copyright: {\textcopyright} 2025, Shen et al.",

year = "2025",

month = mar,

day = "17",

doi = "10.1172/JCI185278",

language = "英语",

volume = "135",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

number = "6",

}

Shen, S, Zhang, Q, Wang, Y, Chen, H, Gong, S, Liu, Y, Gai, C, Chen, H, Zhu, E, Yang, B, Liu, L, Cao, S, Zhao, M, Ren, W, Li, M, Peng, Z, Zhang, L, Zhang, S, Shen, J, Zhang, B, Lee, PKH, Li, K , Li, L & Yang, H 2025, 'Targeting ubiquitin-independent proteasome with small molecule increases susceptibility in pan-KRAS–mutant cancer models', Journal of Clinical Investigation, vol. 135, no. 6, e185278. https://doi.org/10.1172/JCI185278

TY - JOUR

T1 - Targeting ubiquitin-independent proteasome with small molecule increases susceptibility in pan-KRAS–mutant cancer models

AU - Shen, Shihui

AU - Zhang, Qiansen

AU - Wang, Yuhan

AU - Chen, Hui

AU - Gong, Shuangming

AU - Liu, Yun

AU - Gai, Conghao

AU - Chen, Hansen

AU - Zhu, Enhao

AU - Yang, Bo

AU - Liu, Lin

AU - Cao, Siyuan

AU - Zhao, Mengting

AU - Ren, Wenjie

AU - Li, Mengjuan

AU - Peng, Zhuoya

AU - Zhang, Lu

AU - Zhang, Shaoying

AU - Shen, Juwen

AU - Zhang, Bianhong

AU - Lee, Patrick K.H.

AU - Li, Kun

AU - Li, Lei

AU - Yang, Huaiyu

PY - 2025/3/17

Y1 - 2025/3/17

N2 - 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 panKRAS 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.

AB - 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 panKRAS 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.

UR - https://www.scopus.com/pages/publications/105000739267

U2 - 10.1172/JCI185278

DO - 10.1172/JCI185278

M3 - 文章

C2 - 40091835

AN - SCOPUS:105000739267

SN - 0021-9738

VL - 135

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 6

M1 - e185278

ER -

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

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this