RT Journal Article
SR Electronic
T1 A molecule inducing androgen receptor degradation and selectively targeting prostate cancer cells
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201800213
DO 10.26508/lsa.201800213
VO 2
IS 4
A1 Serge Auvin
A1 Harun Öztürk
A1 Yusuf T Abaci
A1 Gisele Mautino
A1 Florence Meyer-Losic
A1 Florence Jollivet
A1 Tarig Bashir
A1 Hugues de Thé
A1 Umut Sahin
YR 2019
UL https://www.life-science-alliance.org/content/2/4/e201800213.abstract
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.