Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer

  • Cell Chem Biol. 2024 Oct 1:S2451-9456(24)00396-9. doi: 10.1016/j.chembiol.2024.09.004.
Sasikumar Kotagiri  1 ,  Nicholas Blazanin  1 ,  Yuanxin Xi  2 ,  Yanyan Han  1 ,  Md Qudratullah  1 ,  Xiaobing Liang  1 ,  Yawen Wang  1 ,  Poonam Pandey  1 ,  Hira Mazhar  1 ,  Truong Nguyen Lam  3 ,  Anand Kamal Singh  4 ,  Jing Wang  2 ,  Yonathan Lissanu  5
Affiliations
  • 1. Department of Cardiovascular and Thoracic Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 2. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 3. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 4. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 5. Department of Cardiovascular and Thoracic Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: [email protected].
PMID: 39378885 DOI: 10.1016/j.chembiol.2024.09.004
Abstract

Genomic studies have identified frequent mutations in subunits of the SWI/SNF (switch/sucrose non-fermenting) chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung Cancer (NSCLC). Genetic evidence indicates that the paralog SMARCA2 is synthetic lethal to SMARCA4 suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. Here, we utilized structure-activity relationship (SAR) studies to develop YD23, a potent and selective proteolysis targeting chimera (PROTAC) targeting SMARCA2. Mechanistically, we show that SMARCA2 degradation induces reprogramming of the enhancer landscape in SMARCA4-mutant cells with loss of chromatin accessibility at enhancers of genes involved in cell proliferation. Furthermore, we identified YAP/TEADas key partners to SMARCA2 in driving growth of SMARCA4-mutant cells. Finally, we show that YD23 has potent tumor growth inhibitory activity in SMARCA4-mutant xenografts. These findings provide the mechanistic basis for development of SMARCA2 degraders as synthetic lethal therapeutics against SMARCA4-mutant lung cancers.

Keywords
PROTAC; SMARCA2; SMARCA4; SWI/SNF; YAP/TEAD; cell cycle; enhancer accessibility; gene regulation; lung cancer; synthetic lethality.
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