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

Sasikumar Kotagiri; Nicholas Blazanin; Yuanxin Xi; Yanyan Han; Md Qudratullah; Xiaobing Liang; Yawen Wang; Poonam Pandey; Hira Mazhar; Truong Nguyen Lam; Anand Kamal Singh; Jing Wang; Yonathan Lissanu

doi:10.1016/j.chembiol.2024.09.004

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. Online ahead of print.

Authors

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.