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Context-Specific Efficacy of Apalutamide Therapy in Preclinical Models of Pten -Deficient Prostate Cancer.

Authors :
De Velasco MA
Kura Y
Ando N
Sako N
Banno E
Fujita K
Nozawa M
Yoshimura K
Sakai K
Yoshikawa K
Nishio K
Uemura H
Source :
Cancers [Cancers (Basel)] 2021 Aug 06; Vol. 13 (16). Date of Electronic Publication: 2021 Aug 06.
Publication Year :
2021

Abstract

Significant improvements with apalutamide, a nonsteroidal antiandrogen used to treat patients suffering from advanced prostate cancer (PCa), have prompted evaluation for additional indications and therapeutic development with other agents; however, persistent androgen receptor (AR) signaling remains problematic. We used autochthonous mouse models of Pten -deficient PCa to examine the context-specific antitumor activity of apalutamide and profile its molecular responses. Overall, apalutamide showed potent antitumor activity in both early-stage and late-stage models of castration-naïve prostate cancer (CNPC). Molecular profiling by Western blot and immunohistochemistry associated persistent surviving cancer cells with upregulated AKT signaling. While apalutamide was ineffective in an early-stage model of castration-resistant prostate cancer (CRPC), it tended to prolong survival in late-stage CRPC. Molecular features associated with surviving cancer cells in CRPC included upregulated aberrant-AR, and phosphorylated S6 and proline-rich Akt substrate of 40 kDa (PRAS40). Strong synergy was observed with the pan-AKT inhibitor GSK690693 and apalutamide in vitro against the CNPC- and CRPC-derived cell lines and tended to improve the antitumor responses in CNPC but not CRPC in vivo. Upregulation of signal transducer and activator of transcription 3 (STAT3) and proviral insertion in murine-1 (PIM-1) were associated with combined apalutamide/GSK690693. Our findings show that apalutamide can attenuate Pten -deficient PCa in a context-specific manner and provides data that can be used to further study and, possibly, develop additional combinations with apalutamide.

Details

Language :
English
ISSN :
2072-6694
Volume :
13
Issue :
16
Database :
MEDLINE
Journal :
Cancers
Publication Type :
Academic Journal
Accession number :
34439133
Full Text :
https://doi.org/10.3390/cancers13163975