Targeting the mSWI/SNF complex in POU2F-POU2AF transcription factor-driven malignancies

  • Cancer Cell. 2024 Aug 12;42(8):1336-1351.e9. doi: 10.1016/j.ccell.2024.06.006.
Tongchen He  1 ,  Lanbo Xiao  2 ,  Yuanyuan Qiao  3 ,  Olaf Klingbeil  4 ,  Eleanor Young  5 ,  Xiaoli S Wu  4 ,  Rahul Mannan  5 ,  Somnath Mahapatra  5 ,  Esther Redin  6 ,  Hanbyul Cho  5 ,  Yi Bao  5 ,  Malathi Kandarpa  7 ,  Jean Ching-Yi Tien  5 ,  Xiaoju Wang  5 ,  Sanjana Eyunni  5 ,  Yang Zheng  5 ,  NamHoon Kim  8 ,  Heng Zheng  5 ,  Siyu Hou  9 ,  Fengyun Su  5 ,  Stephanie J Miner  5 ,  Rohit Mehra  5 ,  Xuhong Cao  10 ,  Chandrasekhar Abbineni  11 ,  Susanta Samajdar  11 ,  Murali Ramachandra  11 ,  Saravana M Dhanasekaran  5 ,  Moshe Talpaz  7 ,  Abhijit Parolia  12 ,  Charles M Rudin  13 ,  Christopher R Vakoc  4 ,  Arul M Chinnaiyan  14
Affiliations
  • 1. 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.
  • 2. 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: [email protected].
  • 3. 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.
  • 4. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
  • 5. Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 6. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 7. 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.
  • 8. Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 9. Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
  • 10. 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.
  • 11. Aurigene Oncology Limited, Bangalore 560100, India.
  • 12. 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, MI 48109, USA.
  • 13. 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.
  • 14. 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, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: [email protected].
PMID: 39029462 DOI: 10.1016/j.ccell.2024.06.006
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.

Keywords
IRF4; POU2AF1/2/3; POU2F3; PROTAC; SCLC; SMARCA2/4; mSWI/SNF complex; multiple myeloma; proteolysis targeting chimera; small cell lung cancer.
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