PT  - JOURNAL ARTICLE
AU  - Auvin, Serge
AU  - Öztürk, Harun
AU  - Abaci, Yusuf T
AU  - Mautino, Gisele
AU  - Meyer-Losic, Florence
AU  - Jollivet, Florence
AU  - Bashir, Tarig
AU  - de Thé, Hugues
AU  - Sahin, Umut
TI  - A molecule inducing androgen receptor degradation and selectively targeting prostate cancer cells
AID  - 10.26508/lsa.201800213
DP  - 2019 Aug 01
TA  - Life Science Alliance
PG  - e201800213
VI  - 2
IP  - 4
4099  - http://www.life-science-alliance.org/content/2/4/e201800213.short
4100  - http://www.life-science-alliance.org/content/2/4/e201800213.full
SO  - Life Sci. Alliance2019 Aug 01; 2
AB  - Aberrant androgen signaling drives prostate cancer and is targeted by drugs that diminish androgen production or impede androgen–androgen receptor (AR) interaction. Clinical resistance arises from AR overexpression or ligand-independent constitutive activation, suggesting that complete AR elimination could be a novel therapeutic strategy in prostate cancers. IRC117539 is a new molecule that targets AR for proteasomal degradation. Exposure to IRC117539 promotes AR sumoylation and ubiquitination, reminiscent of therapy-induced PML/RARA degradation in acute promyelocytic leukemia. Critically, ex vivo, IRC117539-mediated AR degradation induces prostate cancer cell viability loss by inhibiting AR signaling, even in androgen-insensitive cells. This approach may be beneficial for castration-resistant prostate cancer, which remains a clinical issue. In xenograft models, IRC117539 is as potent as enzalutamide in impeding growth, albeit less efficient than expected from ex vivo studies. Unexpectedly, IRC117539 also behaves as a weak proteasome inhibitor, likely explaining its suboptimal efficacy in vivo. Our studies highlight the feasibility of AR targeting for degradation and off-target effects’ importance in modulating drug activity in vivo.