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, Bao Y · 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.

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At a glance

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 type	4 - Animal Study
Model system	ccRCC cell lines (in vitro); mouse xenograft tumors treated with a NEK7-targeting PROTAC
Journal	Nature Communications
Year	2026
Peer reviewed	Yes
Record last updated	2026-09-23
Source	DOI 10.1038/s41467-026-77043-9 · PMID 42778578

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}
}