Enhancer Reprogramming Underlies Therapeutic Utility of a SMARCA2 Degrader in SMARCA4 Mutant Cancer

Authors

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

Language

English

Publication Date

12-19-2024

Journal

Cell Chemical Biology

DOI

10.1016/j.chembiol.2024.09.004

PMID

39378885

PMCID

PMC11663135

PubMedCentral® Posted Date

12-19-2025

PubMedCentral® Full Text Version

Author MSS

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

Humans, Transcription Factors, DNA Helicases, Animals, Nuclear Proteins, Mice, Cell Proliferation, Structure-Activity Relationship, Lung Neoplasms, Antineoplastic Agents, Mutation, Carcinoma, Non-Small-Cell Lung, Mice, Nude, Cell Line, Tumor, Female, Molecular Structure, SMARCA2, SMARCA4, SWI/SNF, PROTAC, lung cancer, YAP, synthetic lethality

Published Open-Access

yes

Recommended Citation

Kotagiri, Sasikumar; Blazanin, Nicholas; Xi, Yuanxin; et al., "Enhancer Reprogramming Underlies Therapeutic Utility of a SMARCA2 Degrader in SMARCA4 Mutant Cancer" (2024). Faculty, Staff and Student Publications. 6174.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6174