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Targeting the mSWI/SNF complex in POU2F-POU2AF transcription factor-driven malignancies.
He, Tongchen; Xiao, Lanbo; Qiao, Yuanyuan; Klingbeil, Olaf; Young, Eleanor; Wu, Xiaoli S; Mannan, Rahul; Mahapatra, Somnath; Redin, Esther; Cho, Hanbyul; Bao, Yi; Kandarpa, Malathi; Ching-Yi Tien, Jean; Wang, Xiaoju; Eyunni, Sanjana; Zheng, Yang; Kim, NamHoon; Zheng, Heng; Hou, Siyu; Su, Fengyun; Miner, Stephanie J; Mehra, Rohit; Cao, Xuhong; Abbineni, Chandrasekhar; Samajdar, Susanta; Ramachandra, Murali; Dhanasekaran, Saravana M; Talpaz, Moshe; Parolia, Abhijit; Rudin, Charles M; Vakoc, Christopher R; Chinnaiyan, Arul M.
Afiliación
  • He T; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
  • Xiao L; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: lanbox@med.umich.edu.
  • Qiao Y; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
  • Klingbeil O; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
  • Young E; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Wu XS; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
  • Mannan R; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Mahapatra S; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Redin E; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Cho H; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Bao Y; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Kandarpa M; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Ching-Yi Tien J; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Wang X; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Eyunni S; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Zheng Y; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Kim N; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Zheng H; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Hou S; Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
  • Su F; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Miner SJ; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Mehra R; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Cao X; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA.
  • Abbineni C; Aurigene Oncology Limited, Bangalore 560100, India.
  • Samajdar S; Aurigene Oncology Limited, Bangalore 560100, India.
  • Ramachandra M; Aurigene Oncology Limited, Bangalore 560100, India.
  • Dhanasekaran SM; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Talpaz M; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Parolia A; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan, Ann Arbor, M
  • Rudin CM; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medicine Graduate School of Medicine Sciences, New York, NY 10065, USA.
  • Vakoc CR; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
  • Chinnaiyan AM; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, University of Michigan, An
Cancer Cell ; 42(8): 1336-1351.e9, 2024 Aug 12.
Article en En | MEDLINE | ID: mdl-39029462
ABSTRACT
The POU2F3-POU2AF2/3 transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we identify a specific dependence of the POU2F3 molecular subtype of SCLC (SCLC-P) on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. Treatment of SCLC-P cells with a proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases evicts POU2F3 and its coactivators from chromatin and attenuates downstream signaling. B cell malignancies which are dependent on the POU2F1/2 cofactor, POU2AF1, are also sensitive to mSWI/SNF ATPase degraders, with treatment leading to chromatin eviction of POU2AF1 and IRF4 and decreased IRF4 signaling in multiple myeloma cells. An orally bioavailable mSWI/SNF ATPase degrader significantly inhibits tumor growth in preclinical models of SCLC-P and multiple myeloma without signs of toxicity. This study suggests that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Carcinoma Pulmonar de Células Pequeñas / Neoplasias Pulmonares Límite: Animals / Humans Idioma: En Revista: Cancer Cell Asunto de la revista: NEOPLASIAS Año: 2024 Tipo del documento: Article País de afiliación: China
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Carcinoma Pulmonar de Células Pequeñas / Neoplasias Pulmonares Límite: Animals / Humans Idioma: En Revista: Cancer Cell Asunto de la revista: NEOPLASIAS Año: 2024 Tipo del documento: Article País de afiliación: China