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Updated: May 22, 2025

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

Shihui Shen1,2, Qiansen Zhang1, Yuhan Wang1

  • 1Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.

The Journal of Clinical Investigation
|March 17, 2025
PubMed

Insights

Researchers found that REGγ is a key factor in KRAS-mutant cancers, driving resistance to therapies. Inhibiting the REGγ-proteasome pathway with RLY01 shows promise for treating these difficult-to-treat cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • KRAS-mutant cancers display resistance to current therapies.
  • Identifying novel therapeutic targets is crucial for improving treatment outcomes.

Purpose of the Study:

  • To identify mutant KRAS-associated factors.
  • To investigate the role of the REGγ-proteasome pathway in KRAS-mutant cancers.
  • To develop novel therapeutic strategies targeting this pathway.

Main Methods:

  • Identification of REGγ as a mutant KRAS-associated factor.
  • Elucidation of the KRAS/NRF2/REGγ regulatory axis.
  • Development and testing of RLY01, a REGγ-proteasome inhibitor.
  • Evaluation of RLY01 in combination with AMG510 in preclinical cancer models.

Main Results:

  • REGγ transcription is enhanced by mutant KRAS via the NRF2 intermediate.
  • The KRAS/NRF2/REGγ axis links activated KRAS to the ATP- and ubiquitin-independent proteasome.
  • RLY01 suppressed tumor growth in KRAS-mutant cancer models and lung cancer organoids.
  • Combination therapy with RLY01 and AMG510 demonstrated enhanced antitumor efficacy.

Conclusions:

  • Mutant KRAS enhances REGγ expression, increasing REGγ-proteasome capacity.
  • Targeting the REGγ-proteasome pathway offers a potential therapeutic strategy for pan-KRAS-mutant cancers.
  • Ubiquitin-independent proteasome inhibition represents a promising approach for treating KRAS-driven malignancies.
Keywords:
CancerDrug therapyOncologyTherapeuticsTumor suppressors

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