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Chronologically modified androgen receptor in recurrent castration-resistant prostate cancer and its therapeutic targeting.
Sawant, Mithila; Mahajan, Kiran; Renganathan, Arun; Weimholt, Cody; Luo, Jingqin; Kukshal, Vandna; Jez, Joseph M; Jeon, Myung Sik; Zhang, Bo; Li, Tiandao; Fang, Bin; Luo, Yunting; Lawrence, Nicholas J; Lawrence, Harshani R; Feng, Felix Y; Mahajan, Nupam P.
Afiliación
  • Sawant M; Department of Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA.
  • Mahajan K; Division of Urologic Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA.
  • Renganathan A; Department of Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA.
  • Weimholt C; Division of Urologic Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA.
  • Luo J; Siteman Cancer Center, Washington University in St. Louis, Cancer Research Building, 660 Euclid Ave., St. Louis, MO 63110, USA.
  • Kukshal V; Department of Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA.
  • Jez JM; Division of Urologic Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA.
  • Jeon MS; Department of Anatomic and Clinical Pathology, Washington University in St. Louis, St. Louis, MO 63110, USA.
  • Zhang B; Department of Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA.
  • Li T; Siteman Cancer Center, Washington University in St. Louis, Cancer Research Building, 660 Euclid Ave., St. Louis, MO 63110, USA.
  • Fang B; Department of Biology, Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63110, USA.
  • Luo Y; Department of Biology, Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63110, USA.
  • Lawrence NJ; Siteman Cancer Center, Washington University in St. Louis, Cancer Research Building, 660 Euclid Ave., St. Louis, MO 63110, USA.
  • Lawrence HR; Bioinformatics Research Core, Center of Regenerative Medicine, Department of Developmental Biology, Washington University in St. Louis, St. Louis, MO 63110, USA.
  • Feng FY; Bioinformatics Research Core, Center of Regenerative Medicine, Department of Developmental Biology, Washington University in St. Louis, St. Louis, MO 63110, USA.
  • Mahajan NP; Drug Discovery Department, Moffitt Cancer Center, Department of Oncologic Sciences, University of South Florida, 12902 USF Magnolia Drive, Tampa, FL 33612, USA.
Sci Transl Med ; 14(649): eabg4132, 2022 06 15.
Article en En | MEDLINE | ID: mdl-35704598
ABSTRACT
Resistance to second-generation androgen receptor (AR) antagonists such as enzalutamide is an inevitable consequence in patients with castration-resistant prostate cancer (CRPC). There are no effective therapeutic options for this recurrent disease. The expression of truncated AR variant 7 (AR-V7) has been suggested to be one mechanism of resistance; however, its low frequency in patients with CRPC does not explain the almost universal acquisition of resistance. We noted that the ability of AR to translocate to nucleus in an enzalutamide-rich environment opens up the possibility of a posttranslational modification in AR that is refractory to enzalutamide binding. Chemical proteomics in enzalutamide-resistant CRPC cells revealed acetylation at Lys609 in the zinc finger DNA binding domain of AR (acK609-AR) that not only allowed AR translocation but also galvanized a distinct global transcription program, conferring enzalutamide insensitivity. Mechanistically, acK609-AR was recruited to the AR and ACK1/TNK2 enhancers, up-regulating their transcription. ACK1 kinase-mediated AR Y267 phosphorylation was a prerequisite for AR K609 acetylation, which spawned positive feedback loops at both the transcriptional and posttranslational level that regenerated and sustained high AR and ACK1 expression. Consistent with these findings, oral and subcutaneous treatment with ACK1 small-molecule inhibitor, (R)-9b, not only curbed AR Y267 phosphorylation and subsequent K609 acetylation but also compromised enzalutamide-resistant CRPC xenograft tumor growth in mice. Overall, these data uncover chronological modification events in AR that allows prostate cancer to evolve through progressive stages to reach the resilient recurrent CRPC stage, opening up a therapeutic vulnerability.
Asunto(s)

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Receptores Androgénicos / Neoplasias de la Próstata Resistentes a la Castración Límite: Animals / Humans / Male Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Receptores Androgénicos / Neoplasias de la Próstata Resistentes a la Castración Límite: Animals / Humans / Male Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos