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- Title
Context-Specific Efficacy of Apalutamide Therapy in Preclinical Models of Pten -Deficient Prostate Cancer.
- Authors
De Velasco, Marco A.; Kura, Yurie; Ando, Naomi; Sako, Noriko; Banno, Eri; Fujita, Kazutoshi; Nozawa, Masahiro; Yoshimura, Kazuhiro; Sakai, Kazuko; Yoshikawa, Kazuhiro; Nishio, Kazuto; Uemura, Hirotsugu
- Abstract
Simple Summary: Next-generation antiandrogens have transformed the therapeutic landscape for castration-resistant prostate cancer. Their utility in other indications, such as high-risk castration-sensitive cancers and as combination therapy, are being investigated. Our aim was to profile the in vivo antitumor activity of apalutamide in phenotypically distinct mouse models of Pten-deficient castration-naïve and castration-resistant prostate cancer, using both early- and late-stage disease models, and to profile the molecular responses. We also evaluated the therapeutic potential and characterized the molecular responses of the combined targeted AR/AKT blockade and showed that while this approach was promising in vitro, it was mostly ineffective in vivo, particularly in the castration-resistant setting. Our findings provide evidence that links therapeutic resistance to STAT3 and PIM-1 in the castration-resistant setting and provide insights into the context-specific antitumor activity of apalutamide. 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.
- Subjects
DRUG efficacy; BIOLOGICAL models; IN vitro studies; STAT proteins; ANTIANDROGENS; CLINICAL drug trials; IN vivo studies; ANIMAL experimentation; WESTERN immunoblotting; IMMUNOHISTOCHEMISTRY; ANTINEOPLASTIC agents; PHOSPHATASES; TUMOR classification; CELLULAR signal transduction; TRANSFERASES; DRUG development; CELL lines; PROSTATE tumors; MICE; PHARMACODYNAMICS
- Publication
Cancers, 2021, Vol 13, Issue 16, p3975
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers13163975