Anti-Androgen Therapy Radiosensitizes Androgen Receptor Positive Cancers to F-18 Fluorodeoxyglucose

Driver genes with a mutually exclusive mutation pattern across tumor genomes are thought to have overlapping roles in tumorigenesis. In contrast, we show here that mutually-exclusive prostate cancer driver alterations involving the ERG transcription factor and the ubiquitin ligase adaptor SPOP are synthetic sick. At the molecular level, the incompatible cancer pathways are driven by opposing functions in SPOP. ERG up-regulates wild type SPOP to dampen androgen receptor (AR) signaling and sustain ERG activity through degradation of the bromodomain histone reader ZMYND11. Conversely, SPOP-mutant tumors stabilize ZMYND11 to repress ERG-function and enable oncogenic androgen receptor signaling. This dichotomy regulates the response to therapeutic interventions in the AR pathway. While mutant SPOP renders tumor cells susceptible to androgen deprivation therapies, ERG promotes sensitivity to high-dose androgen therapy and pharmacological inhibition of wild type SPOP. More generally, these results define a distinct class of antagonistic cancer drivers and a blueprint toward their therapeutic exploitation.

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Bipolar androgen therapy sensitizes castration-resistant prostate cancer to subsequent androgen receptor ablative therapy

European Journal of Cancer ◽

10.1016/j.ejca.2020.11.043 ◽

2021 ◽

Vol 144 ◽

pp. 302-309

Author(s):

Laura A. Sena ◽

Hao Wang ◽

Su J. Lim ScM ◽

Irina Rifkind ◽

Nduku Ngomba ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Castration Resistant Prostate Cancer ◽

Androgen Therapy ◽

Ablative Therapy ◽

Castration Resistant

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MP92-12 ANTI-ANDROGEN THERAPY SUPPRESSES TUMOR GROWTH IN ANDROGEN RECEPTOR-POSITIVE RENAL CELL CARCINOMA: A XENOGRAFT STUDY

The Journal of Urology ◽

10.1016/j.juro.2016.02.2645 ◽

2016 ◽

Vol 195 (4S) ◽

Author(s):

Christopher Han ◽

Geun Taek Lee ◽

Rutveej Patel ◽

Parth Modi ◽

Seok Joo Kwon ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Androgen Receptor ◽

Tumor Growth ◽

Cell Carcinoma ◽

Renal Cell ◽

Androgen Therapy

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Dual functions of SPOP and ERG dictate androgen therapy responses in prostate cancer

Nature Communications ◽

10.1038/s41467-020-20820-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Tiziano Bernasocchi ◽

Geniver El Tekle ◽

Marco Bolis ◽

Azzurra Mutti ◽

Arianna Vallerga ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Therapeutic Interventions ◽

High Dose ◽

Wild Type ◽

Driver Genes ◽

Androgen Therapy ◽

Cancer Driver ◽

Cancer Pathways ◽

Mutation Pattern

AbstractDriver genes with a mutually exclusive mutation pattern across tumor genomes are thought to have overlapping roles in tumorigenesis. In contrast, we show here that mutually exclusive prostate cancer driver alterations involving the ERG transcription factor and the ubiquitin ligase adaptor SPOP are synthetic sick. At the molecular level, the incompatible cancer pathways are driven by opposing functions in SPOP. ERG upregulates wild type SPOP to dampen androgen receptor (AR) signaling and sustain ERG activity through degradation of the bromodomain histone reader ZMYND11. Conversely, SPOP-mutant tumors stabilize ZMYND11 to repress ERG-function and enable oncogenic androgen receptor signaling. This dichotomy regulates the response to therapeutic interventions in the AR pathway. While mutant SPOP renders tumor cells susceptible to androgen deprivation therapies, ERG promotes sensitivity to high-dose androgen therapy and pharmacological inhibition of wild type SPOP. More generally, these results define a distinct class of antagonistic cancer drivers and a blueprint toward their therapeutic exploitation.

Download Full-text