A combinatorial screen of the CLOUD uncovers a synergy targeting the androgen receptor
Marco Licciardello
(1)
,
Anna Ringler
(1)
,
Patrick Markt
(1)
,
Freya Klepsch
(1)
,
Charles-Hugues Lardeau
(1)
,
Sara Sdelci
(1)
,
Erika Schirghuber
(2, 1)
,
André Müller
(3, 1)
,
Michael Caldera
(1)
,
Anja Wagner
(4, 5)
,
Rebecca Herzog
(5)
,
Thomas Penz
(1)
,
Michael Schuster
(6, 1)
,
Bernd Boidol
(1)
,
Gerhard Dürnberger
(7, 8)
,
Yasin Folkvaljon
(9)
,
Pär Stattin
(10)
,
Vladimir Ivanov
(11)
,
Jacques Colinge
(7)
,
Christoph Bock
(12, 1)
,
Klaus Kratochwill
(1)
,
Jörg Menche
(1)
,
Keiryn Bennett
(1)
,
Stefan Kubicek
(1)
1
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria
2 IMP - Research Institute of Molecular Pathology
3 ESEP - Economies, sociétés et environnements préhistoriques
4 Gastroenterology & Hepatology
5 Medizinische Universität Wien = Medical University of Vienna
6 FuMATech
7 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
8 CeMM - Research Center for Molecular Medicine of the Austrian Academy of Sciences [Vienna, Austria]
9 Nus - Umeå University Hospital = Norrlands universitetssjukhus
10 Department of Surgical and Perioperative Sciences, Urology and Andrology
11 Enamine Ltd
12 Max Planck Institute for Informatics [Saarbrücken]
2 IMP - Research Institute of Molecular Pathology
3 ESEP - Economies, sociétés et environnements préhistoriques
4 Gastroenterology & Hepatology
5 Medizinische Universität Wien = Medical University of Vienna
6 FuMATech
7 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
8 CeMM - Research Center for Molecular Medicine of the Austrian Academy of Sciences [Vienna, Austria]
9 Nus - Umeå University Hospital = Norrlands universitetssjukhus
10 Department of Surgical and Perioperative Sciences, Urology and Andrology
11 Enamine Ltd
12 Max Planck Institute for Informatics [Saarbrücken]
Jacques Colinge
- Fonction : Auteur
- PersonId : 184393
- IdHAL : jacques-colinge
- ORCID : 0000-0003-2466-4824
Résumé
Approved drugs are invaluable tools to study biochemical pathways, and further characterization of these compounds may lead to repurposing of single drugs or combinations. Here we describe a collection of 308 small molecules representing the diversity of structures and molecular targets of all FDA-approved chemical entities. The CeMM Library of Unique Drugs (CLOUD) covers prodrugs and active forms at pharmacologically relevant concentrations and is ideally suited for combinatorial studies. We screened pairwise combinations of CLOUD drugs for impairment of cancer cell viability and discovered a synergistic interaction between flutamide and phenprocoumon (PPC). The combination of these drugs modulates the stability of the androgen receptor (AR) and resensitizes AR-mutant prostate cancer cells to flutamide. Mechanistically, we show that the AR is a substrate for γ-carboxylation, a post-translational modification inhibited by PPC. Collectively, our data suggest that PPC could be repurposed to tackle resistance to antiandrogens in prostate cancer patients.