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Exquisite Sensitivity to Dual BRG1/BRM ATPase Inhibitors Reveals Broad SWI/SNF Dependencies in Acute Myeloid Leukemia
Florencia Rago1, Lindsey Ulkus Rodrigues1, Megan Bonney1
1Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Abstract:
Various subunits of mammalian SWI/SNF chromatin remodeling complexes display loss-of-function mutations characteristic of tumor suppressors in different cancers, but an additional role for SWI/SNF supporting cell survival in distinct cancer contexts is emerging. In particular, genetic dependence on the catalytic subunit BRG1/SMARCA4 has been observed in acute myelogenous leukemia (AML), yet the feasibility of direct therapeutic targeting of SWI/SNF catalytic activity in leukemia remains unknown. Here, we evaluated the activity of dual BRG1/BRM ATPase inhibitors across a genetically diverse panel of cancer cell lines and observed that hematopoietic cancer cell lines were among the most sensitive compared with other lineages. This result was striking in comparison with data from pooled short hairpin RNA screens, which showed that only a subset of leukemia cell lines display sensitivity to BRG1 knockdown. We demonstrate that combined genetic knockdown of BRG1 and BRM is required to recapitulate the effects of dual inhibitors, suggesting that SWI/SNF dependency in human leukemia extends beyond a predominantly BRG1-driven mechanism. Through gene expression and chromatin accessibility studies, we show that the dual inhibitors act at genomic loci associated with oncogenic transcription factors, and observe a downregulation of leukemic pathway genes, including MYC, a well-established target of BRG1 activity in AML. Overall, small-molecule inhibition of BRG1/BRM induced common transcriptional responses across leukemia models resulting in a spectrum of cellular phenotypes.
Implications:
Our studies reveal the breadth of SWI/SNF dependency in leukemia and support targeting SWI/SNF catalytic function as a potential therapeutic strategy in AML.
Insights
Targeting SWI/SNF (Switch/Sucrose Non-Fermentable) complexes with dual BRG1/BRM inhibitors shows promise for treating acute myelogenous leukemia (AML). This approach reveals a broader dependency than previously understood, offering a new therapeutic strategy.
Area of Science:
- Cancer Biology
- Epigenetics
- Chromatin Remodeling
Background:
- Mammalian SWI/SNF complexes are implicated in cancer, with mutations often acting as tumor suppressors.
- Emerging evidence suggests SWI/SNF complexes also support cancer cell survival.
- Genetic dependence on BRG1/SMARCA4 has been noted in acute myelogenous leukemia (AML), but therapeutic targeting remains unexplored.
Purpose of the Study:
- To evaluate the efficacy of dual BRG1/BRM ATPase inhibitors in various cancer cell lines.
- To investigate the mechanism of SWI/SNF dependency in leukemia.
- To explore the therapeutic potential of targeting SWI/SNF catalytic activity in AML.
Main Methods:
- Treatment of diverse cancer cell lines with dual BRG1/BRM ATPase inhibitors.
- Analysis of sensitivity across different cancer lineages, particularly hematopoietic cancers.
- Comparison with short hairpin RNA (shRNA) screening data for BRG1 knockdown.
- Combined genetic knockdown of BRG1 and BRM.
- Gene expression and chromatin accessibility studies.
- Analysis of downstream effects on oncogenic transcription factors and leukemic pathway genes like MYC.
Main Results:
- Hematopoietic cancer cell lines exhibited high sensitivity to dual BRG1/BRM inhibitors.
- Sensitivity to dual inhibitors exceeded that predicted by BRG1 knockdown alone.
- Combined BRG1 and BRM knockdown was necessary to mimic inhibitor effects, indicating broader SWI/SNF dependency.
- Inhibitors targeted loci of oncogenic transcription factors, downregulating key leukemic genes including MYC.
- Consistent transcriptional responses and varied cellular phenotypes were observed across leukemia models.
Conclusions:
- SWI/SNF dependency in leukemia is more extensive than previously recognized.
- Targeting SWI/SNF catalytic function presents a viable therapeutic strategy for AML.
