Opposing effects of cancer-Type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors

Hana Janouskova, Geniver El Tekle, Elisa Bellini, Namrata D. Udeshi, Anna Rinaldi, Anna Ulbricht, Tiziano Bernasocchi, Gianluca Civenni, Marco Losa, Tanya Svinkina, Craig M. Bielski, Gregory V. Kryukov, Luciano Cascione, Sara Napoli, Radoslav I. Enchev, David G. Mutch, Michael E. Carney, Andrew Berchuck, Boris J.N. Winterhoff, Russell R. BroaddusPeter Schraml, Holger Moch, Francesco Bertoni, Carlo V. Catapano, Matthias Peter, Steven A. Carr, Levi A. Garraway, Peter J. Wild, Jean Philippe P. Theurillat

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer-Associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP-CUL3 substrates that are preferentially degraded by endometrial cancer-Associated SPOP mutants. The resulting reduction of BET protein levels sensitized cancer cells to BET inhibitors. Conversely, prostate cancer-specific SPOP mutations resulted in impaired degradation of BETs, promoting their resistance to pharmacologic inhibition. These results uncover an oncogenomics paradox, whereby mutations mapping to the same domain evoke opposing drug susceptibilities. Specifically, we provide a molecular rationale for the use of BET inhibitors to treat patients with endometrial but not prostate cancer who harbor SPOP mutations.

Original languageEnglish (US)
Pages (from-to)1046-1054
Number of pages9
JournalNature Medicine
Volume23
Issue number9
DOIs
StatePublished - Sep 1 2017

Bibliographical note

Funding Information:
We thank M. Losa, M. Storz, P. Schraml, S. Dettwiler and F. Prutek for help with tissue handling and histology assistance. We thank Q. Zhong for his help with the next-generation sequencing bioinformatics pipeline. We thank all members of the IRB animal core facility for technical assistance and the animal work. We thank E. Samartzis and K. Dedes (University Hospital Zurich) for providing AN3CA, HEC1A, HEC1B, HEC116, SNG-II, EFE184 and KLE cell lines. We thank the Oregon Health & Science University (OHSU) and the Cooperative Human Tissue Network (CHTN) for the tissue repository. We also thank all members of the laboratory for scientific discussions. J.-P.P.T. is funded by a Swiss National Science Foundation Professorship (PP00P3_150645) grant, a Swiss Cancer League (KSL-3654-02-2015) grant, a grant by the Jubiläumsstiftung Swiss Life AG and a grant by the Vontobel Stiftung. The Swiss National Science Foundation (310030B_160312/1), the European Research Council (268930), SystemsX IPhD (2013/128), Krebsforschungs Schweiz (KFS-3498-08-2014) and a GRL grant from the Korean government fund M.P. This work was also funded in part by a grant to P.J.W. provided by Oncosuisse (KLS-3384-02-2014-R) and the Foundation for Research in Science and the Humanities at the University of Zurich (SWF).

Publisher Copyright:
© Nature America, Inc., part of Springer Nature. All rights reserved.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

PubMed: MeSH publication types

  • Journal Article

Fingerprint Dive into the research topics of 'Opposing effects of cancer-Type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors'. Together they form a unique fingerprint.

Cite this