Related Experiment Video

Updated: Jun 11, 2025

Engineering Oncogenic Heterozygous Gain-of-Function Mutations in Human Hematopoietic Stem and Progenitor Cells
12:04

Engineering Oncogenic Heterozygous Gain-of-Function Mutations in Human Hematopoietic Stem and Progenitor Cells

Published on: March 10, 2023

3.5K

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

Sasikumar Kotagiri1, Nicholas Blazanin1, Yuanxin Xi2

  • 1Department of Cardiovascular and Thoracic Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Cell Chemical Biology
|October 8, 2024
PubMed

Insights

Targeting SMARCA2 with the novel PROTAC YD23 offers a synthetic lethal strategy for SMARCA4-mutant lung cancers. SMARCA2 degradation disrupts cell proliferation enhancers and inhibits tumor growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Non-small cell lung cancer (NSCLC) frequently harbors mutations in SWI/SNF chromatin remodeling complex subunits like SMARCA4 and ARID1A.
  • SMARCA4-mutant cancers exhibit synthetic lethality with SMARCA2, identifying SMARCA2 as a potential therapeutic target.
  • Developing selective SMARCA2 inhibitors has been a significant challenge in NSCLC treatment.

Purpose of the Study:

  • To develop a potent and selective SMARCA2 degrader using proteolysis targeting chimera (PROTAC) technology.
  • To elucidate the molecular mechanisms by which SMARCA2 degradation impacts chromatin accessibility and gene expression in SMARCA4-mutant cells.
  • To evaluate the therapeutic efficacy of the SMARCA2 degrader in preclinical models of SMARCA4-mutant NSCLC.

Main Methods:

  • Structure-activity relationship (SAR) studies were employed to design and optimize the PROTAC YD23.
  • SMARCA2 degradation was assessed in cancer cells, followed by analysis of chromatin accessibility using ATAC-seq.
  • The role of YAP/TEAD in SMARCA2-mediated growth was investigated, and YD23 efficacy was tested in SMARCA4-mutant xenografts.

Main Results:

  • YD23 was identified as a potent and selective PROTAC that effectively degrades SMARCA2.
  • SMARCA2 degradation led to reprogramming of the enhancer landscape, reducing chromatin accessibility at proliferation-associated genes.
  • The YAP/TEAD pathway was identified as crucial for SMARCA4-mutant cell growth, and YD23 demonstrated significant tumor growth inhibition in vivo.

Conclusions:

  • SMARCA2 degradation by PROTAC YD23 represents a promising synthetic lethal therapeutic strategy for SMARCA4-mutant NSCLC.
  • YD23's mechanism involves altering enhancer accessibility and impacting YAP/TEAD-driven proliferation.
  • These findings support the clinical development of SMARCA2 degraders for treating specific lung cancer subtypes.
Keywords:
PROTACSMARCA2SMARCA4SWI/SNFYAP/TEADcell cycleenhancer accessibilitygene regulationlung cancersynthetic lethality

More Related Videos

A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis07:41

A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis

Published on: March 8, 2022

2.4K
Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells09:37

Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells

Published on: August 25, 2021

1.7K

Related Concept Videos

Somatic to iPS Cell Reprogramming01:29

Somatic to iPS Cell Reprogramming

Reprogramming alters the gene expression in somatic cells, transforming them into induced pluripotent stem (iPS) cells over several generations. Scientists can reprogram cells by introducing genes for four transcription factors—Oct4, Sox2, Klf4, and c-Myc (OSKM) by viral or non-viral methods. These factors are also known as Yamanaka factors after Shinya Yamanaka, who first generated iPS cells using mouse skin cells. Yamanaka was awarded the Nobel Prize in Physiology or Medicine in 2012...
2.2K
Conservative Site-specific Recombination and Phase Variation02:53

Conservative Site-specific Recombination and Phase Variation

Because the DNA segments are cut and reorganized in a direction-specific manner, site-specific recombination has emerged as an efficient genetic engineering technique. Flippase and Cyclization recombinases or Flp and Cre, respectively, are two members of the tyrosine recombinase family derived from bacteriophages, that are used to mediate site-specific DNA insertions, deletions, and targeted expression of proteins in mammalian cell lines.
The recognition sites for Cre recombinase called LoxP...
5.9K
Induced Pluripotent Stem Cells01:06

Induced Pluripotent Stem Cells

Stem cells are undifferentiated cells that divide and produce different cell types. Ordinarily, cells that have differentiated into a specific cell type are terminally differentiated; however, scientists have found a way to reprogram these mature cells so that they dedifferentiate and return to an unspecialized, proliferative state. These cells are pluripotent like embryonic stem cells—able to produce all cell types—and are called induced pluripotent stem cells (iPSCs).
Somatic...
3.9K
Methods of Nuclear Reprogramming01:24

Methods of Nuclear Reprogramming

Nuclear reprogramming is a process of transforming one cell type into an unrelated cell type by epigenetic changes that alter the cell’s original gene expression pattern. Such epigenetic changes force cells to express a different set of genes, which play a significant role in inducing transformation into other cell types. Nuclear reprogramming offers applications in reproductive cloning for livestock propagation and regenerative medicine — developing patient-specific cells for...
1.8K