2. Academic Validation
  3. Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer

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

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: ylissanu@mdanderson.org.
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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