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

Tongchen He; Lanbo Xiao; Yuanyuan Qiao; Olaf Klingbeil; Eleanor Young; Xiaoli S Wu; Rahul Mannan; Somnath Mahapatra; Esther Redin; Hanbyul Cho; Yi Bao; Malathi Kandarpa; Jean Ching-Yi Tien; Xiaoju Wang; Sanjana Eyunni; Yang Zheng; NamHoon Kim; Heng Zheng; Siyu Hou; Fengyun Su; Stephanie J Miner; Rohit Mehra; Xuhong Cao; Chandrasekhar Abbineni; Susanta Samajdar; Murali Ramachandra; Saravana M Dhanasekaran; Moshe Talpaz; Abhijit Parolia; Charles M Rudin; Christopher R Vakoc; Arul M Chinnaiyan

doi:10.1016/j.ccell.2024.06.006

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. Epub 2024 Jul 18.

Authors

Tongchen He¹, Lanbo Xiao², Yuanyuan Qiao³, Olaf Klingbeil⁴, Eleanor Young⁵, Xiaoli S Wu⁴, Rahul Mannan⁵, Somnath Mahapatra⁵, Esther Redin⁶, Hanbyul Cho⁵, Yi Bao⁵, Malathi Kandarpa⁷, Jean Ching-Yi Tien⁵, Xiaoju Wang⁵, Sanjana Eyunni⁵, Yang Zheng⁵, NamHoon Kim⁸, Heng Zheng⁵, Siyu Hou⁹, Fengyun Su⁵, Stephanie J Miner⁵, Rohit Mehra⁵, Xuhong Cao¹⁰, Chandrasekhar Abbineni¹¹, Susanta Samajdar¹¹, Murali Ramachandra¹¹, Saravana M Dhanasekaran⁵, Moshe Talpaz⁷, Abhijit Parolia¹², Charles M Rudin¹³, Christopher R Vakoc⁴, Arul M Chinnaiyan¹⁴

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: lanbox@med.umich.edu.
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: arul@med.umich.edu.

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.

MeSH terms

Animals
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms* / genetics
Lung Neoplasms* / metabolism
Lung Neoplasms* / pathology
Mice
Octamer Transcription Factor-2
Octamer Transcription Factor-3 / genetics
Octamer Transcription Factor-3 / metabolism
Signal Transduction
Small Cell Lung Carcinoma* / genetics
Small Cell Lung Carcinoma* / metabolism
Small Cell Lung Carcinoma* / pathology
Transcription Factors* / genetics
Transcription Factors* / metabolism
Xenograft Model Antitumor Assays

Substances

Transcription Factors
Octamer Transcription Factor-3
POU2F2 protein, human
SMARCA2 protein, human
Octamer Transcription Factor-2

Abstract

MeSH terms

Substances

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