Development of an orally bioavailable mSWI/SNF ATPase degrader and acquired mechanisms of resistance in prostate cancer

  • Proc Natl Acad Sci U S A. 2024 Apr 9;121(15):e2322563121. doi: 10.1073/pnas.2322563121.
Tongchen He  #  1  2  3 ,  Caleb Cheng  #  1  4  5 ,  Yuanyuan Qiao  1  2  6 ,  Hanbyul Cho  1  2 ,  Eleanor Young  1  2 ,  Rahul Mannan  1  2 ,  Somnath Mahapatra  1  2 ,  Stephanie J Miner  1  2 ,  Yang Zheng  1  2 ,  NamHoon Kim  1 ,  Victoria Z Zeng  1 ,  Jasmine P Wisniewski  1 ,  Siyu Hou  7 ,  Bailey Jackson  1 ,  Xuhong Cao  1  2  8 ,  Fengyun Su  1  2 ,  Rui Wang  1  2 ,  Yu Chang  1  2 ,  Bilash Kuila  9 ,  Subhendu Mukherjee  9 ,  Sandeep Dukare  9 ,  Kiran B Aithal  9 ,  Samiulla D S  9 ,  Chandrasekhar Abbineni  9 ,  Ulka Vaishampayan  6  10 ,  Costas A Lyssiotis  6  11  12 ,  Abhijit Parolia  1  2  6 ,  Lanbo Xiao  1  2  6 ,  Arul M Chinnaiyan  1  2  6  8  13
Affiliations
  • 1. Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109.
  • 2. Department of Pathology, University of Michigan, Ann Arbor, MI 48109.
  • 3. Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
  • 4. Medical Scientist Training Program, University of Michigan, Ann Arbor, MI 48109.
  • 5. Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109.
  • 6. Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109.
  • 7. Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI 48109.
  • 8. HHMI, University of Michigan, Ann Arbor, MI 48109.
  • 9. Aurigene Oncology Limited, Bangalore, Karnataka 560100, India.
  • 10. Department of Internal Medicine, Division of Medical Oncology, University of Michigan, Ann Arbor, MI 48109.
  • 11. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109.
  • 12. Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109.
  • 13. Department of Urology, University of Michigan, Ann Arbor, MI 48109.
  • # Contributed equally.
PMID: 38557192 DOI: 10.1073/pnas.2322563121
Abstract

Mammalian switch/sucrose nonfermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, an orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of Castration-Resistant Prostate Cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care Androgen Receptor (AR) antagonist used in CRPC patients. Importantly, AU-24118 exhibited favorable pharmacokinetic profiles in preclinical analyses in mice and rats, and further toxicity testing in mice showed a favorable safety profile. As acquired resistance is common with targeted Cancer therapeutics, experiments were designed to explore potential mechanisms of resistance that may arise with long-term mSWI/SNF ATPase PROTAC treatment. Prostate Cancer cell lines exposed to long-term treatment with high doses of a mSWI/SNF ATPase degrader developed SMARCA4 bromodomain mutations and ABCB1 (ATP binding cassette subfamily B member 1) overexpression as acquired mechanisms of resistance. Intriguingly, while SMARCA4 mutations provided specific resistance to mSWI/SNF degraders, ABCB1 overexpression provided broader resistance to other potent PROTAC degraders targeting bromodomain-containing protein 4 and AR. The ABCB1 inhibitor, zosuquidar, reversed resistance to all three PROTAC degraders tested. Combined, these findings position mSWI/SNF degraders for clinical translation for patients with enhancer-driven cancers and define strategies to overcome resistance mechanisms that may arise.

Keywords
ABCB1; SMARCA2; SMARCA4; mSWI/SNF; proteolysis-targeting chimera (PROTAC).
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