Oliver's mTOR Atlas Evidence Platform
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SPOP-mediated ZMYND8 ubiquitination and phase separation exclusion drives mTOR inhibitor resistance in kidney cancer

Tang B, Sun R, Shao J, Wu QY, Yan Y, Wang D, Yu Z, Hu L, Chen Y, Liao C, Wei Q, …, Huang H · 2026 · Nature Communications · Atlas ID TAN2026

What this study shows

Identifies a mechanism of mTOR-inhibitor (everolimus/temsirolimus) resistance in clear cell renal cell carcinoma: SPOP-driven K63-linked ubiquitination of ZMYND8 excludes it from phase-separation compartments, enabling a ZMYND8-ZHX2 complex that drives NEK7 transcription and alternative p70S6K activation independent of mTOR inhibition. A NEK7-targeting PROTAC restored everolimus sensitivity in ccRCC cells and mouse tumors, nominating NEK7 as a target to overcome mTOR-inhibitor resistance.

Abstract

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mTOR inhibitors including everolimus and temsirolimus have been approved by US FDA for treatment of clear cell renal cell carcinoma (ccRCC) in clinic. However, resistance to these drugs has been inevitable and the underlying mechanism remains poorly understood. Histone modifier ZMYND8 paradoxically acts as a transcription coactivator or corepressor.

Read the full abstract on PubMed →

At a glance

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Evidence type A Animal model Marked A because it is an animal intervention or observation study measuring an organismal outcome (model: ccRCC cell lines (in vitro); mouse xenograft tumors treated with a NEK7-targeting PROTAC); the code names the system studied -- animal work can be rigorous and still not be human data.
Study type4 - Animal Study
Model systemccRCC cell lines (in vitro); mouse xenograft tumors treated with a NEK7-targeting PROTAC
JournalNature Communications
Year2026
Peer reviewedYes
Record last updated2026-10-01
SourceDOI 10.1038/s41467-026-77043-9 · PMID 42778578

Where this study fits

How this study connects to the pathway map, open questions, people and other studies in the Atlas.

People in the Atlas

  • Bo Tang first author · 1 study in the Atlas

    Urology researcher at West China Hospital and first author of a study explaining how kidney cancers escape mTOR inhibitor drugs, and how blocking NEK7 restores their effect

  • Haojie Huang last author · 1 study in the Atlas

    Senior/corresponding author of a 2026 Nature Communications study identifying the SPOP–ZMYND8–NEK7 mechanism of mTOR-inhibitor resistance in kidney cancer

More: 11 other authors

No profile yet: Sun R, Shao J, Wu QY, Yan Y, Wang D, Yu Z, Hu L, Chen Y, Liao C, Wei Q, Bao Y

Related studies

More related studies

All 40 studies on S6K1

Topics

Renal cell carcinoma (RCC)EverolimusTemsirolimusS6K1

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

InterventionSPOP or NEK7 inhibition, including a NEK7-targeting PROTAC combined with everolimus
TargetSPOP-ZMYND8-ZHX2-NEK7 axis driving p70S6K activation
ModelHuman ccRCC cell lines; mouse xenografts
EffectSPOP-driven ZMYND8 ubiquitination induces NEK7, which activates p70S6K independently of mTOR and confers mTOR-inhibitor resistance; NEK7 degradation restored everolimus sensitivity.

Cite this paper

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Tang, B., Sun, R., Shao, J., Wu, Q. Y., Yan, Y., Wang, D., Yu, Z., Hu, L., Chen, Y., Liao, C., Wei, Q., Bao, Y., & Huang, H. (2026). SPOP-mediated ZMYND8 ubiquitination and phase separation exclusion drives mTOR inhibitor resistance in kidney cancer. Nature Communications. https://doi.org/10.1038/s41467-026-77043-9

@article{TAN2026,
  author       = {Tang, B. and Sun, R. and Shao, J. and Wu, Q. Y. and Yan, Y. and Wang, D. and Yu, Z. and Hu, L. and Chen, Y. and Liao, C. and Wei, Q. and Bao, Y. and Huang, H.},
  title        = {{SPOP-mediated ZMYND8 ubiquitination and phase separation exclusion drives mTOR inhibitor resistance in kidney cancer}},
  journal      = {Nature Communications},
  year         = {2026},
  doi          = {10.1038/s41467-026-77043-9},
  note         = {PMID: 42778578},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper. 

Barton, O. (2026). Oliver's mTOR Atlas (record TAN2026) [Data set]. https://mtor-atlas.org/study/TAN2026/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_TAN2026,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record TAN2026},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/TAN2026/},
  doi          = {10.5281/zenodo.22059963}
}
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