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

被引:141
作者
Janouskova, Hana [1 ,2 ]
El Tekle, Geniver [1 ,2 ,3 ]
Bellini, Elisa [4 ]
Udeshi, Namrata D. [5 ]
Rinaldi, Anna [1 ,2 ]
Ulbricht, Anna [6 ]
Bernasocchi, Tiziano [1 ,2 ,3 ]
Civenni, Gianluca [1 ,2 ]
Losa, Marco [1 ,2 ]
Svinkina, Tanya [5 ]
Bielski, Craig M. [5 ,14 ]
Kryukov, Gregory V. [5 ]
Cascione, Luciano [1 ,2 ]
Napoli, Sara [1 ,2 ]
Enchev, Radoslav I. [6 ]
Mutch, David G. [7 ]
Carney, Michael E. [8 ]
Berchuck, Andrew [9 ]
Winterhoff, Boris J. N. [10 ]
Broaddus, Russell R. [11 ]
Schraml, Peter [4 ]
Moch, Holger [4 ]
Bertoni, Francesco [1 ,2 ]
Catapano, Carlo V. [1 ,2 ,3 ]
Peter, Matthias [6 ]
Carr, Steven A. [5 ]
Garraway, Levi A. [5 ,12 ,13 ]
Wild, Peter J. [4 ]
Theurillat, Jean-Philippe P. [1 ,2 ,3 ]
机构
[1] Oncol Inst Southern Switzerland, Oncol Res Inst, Bellinzona, Switzerland
[2] Univ Svizzera Italiana, Fac Biomed Sci, Lugano, Switzerland
[3] Univ Lausanne, Ctr Hosp Univ Vaudois, Lausanne, Switzerland
[4] Univ Hosp Zurich, Inst Surg Pathol, Zurich, Switzerland
[5] Broad Inst Harvard & MIT, Cambridge, MA USA
[6] Swiss Fed Inst Technol, Dept Biochem, Zurich, Switzerland
[7] Washington Univ, Div Gynecol Oncol, St Louis, MO USA
[8] Univ Hawaii Manoa, John A Burns Sch Med, Dept Obstet Gynecol & Womens Hlth, Honolulu, HI 96822 USA
[9] Duke Canc Ctr, Div Gynecol Oncol, Durham, NC USA
[10] Univ Minnesota, Div Gynecol Oncol, Minneapolis, MN USA
[11] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA
[12] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
[13] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA
[14] Mem Sloan Kettering Canc Ctr, Mol Oncol, 1275 York Ave, New York, NY 10021 USA
基金
欧洲研究理事会; 瑞士国家科学基金会;
关键词
PROSTATE-CANCER; BREAST-CANCER; BROMODOMAIN INHIBITORS; ENDOMETRIAL CARCINOMAS; GENOMIC LANDSCAPE; UBIQUITIN LIGASE; MUTATIONS; RESISTANCE; RECEPTOR; TUMORS;
D O I
10.1038/nm.4372
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1046 / +
页数:13
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