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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade
Octavio A Romero1, Andrea Vilarrubi2, Juan J Alburquerque-Bejar2
1Cancer Genetics Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Spain. oromero@carrerasresearch.org.
Abstract:
Despite the genetic inactivation of SMARCA4, a core component of the SWI/SNF-complex commonly found in cancer, there are no therapies that effectively target SMARCA4-deficient tumours. Here, we show that, unlike the cells with activated MYC oncogene, cells with SMARCA4 inactivation are refractory to the histone deacetylase inhibitor, SAHA, leading to the aberrant accumulation of H3K27me3. SMARCA4-mutant cells also show an impaired transactivation and significantly reduced levels of the histone demethylases KDM6A/UTX and KDM6B/JMJD3, and a strong dependency on these histone demethylases, so that its inhibition compromises cell viability. Administering the KDM6 inhibitor GSK-J4 to mice orthotopically implanted with SMARCA4-mutant lung cancer cells or primary small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), had strong anti-tumour effects. In this work we highlight the vulnerability of KDM6 inhibitors as a characteristic that could be exploited for treating SMARCA4-mutant cancer patients.
Insights
SMARCA4-mutant cancers are vulnerable to KDM6 inhibitors. This study reveals that inhibiting histone demethylases KDM6A/UTX and KDM6B/JMJD3 effectively targets these tumors, offering a potential new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- SMARCA4 is a core SWI/SNF-complex component frequently inactivated in various cancers.
- Currently, no effective therapies specifically target SMARCA4-deficient tumors.
- SMARCA4 inactivation leads to unique cellular vulnerabilities not seen in other oncogenic contexts.
Purpose of the Study:
- To identify therapeutic vulnerabilities in SMARCA4-deficient cancers.
- To investigate the role of histone demethylases in SMARCA4-mutant cells.
- To evaluate the efficacy of KDM6 inhibitors as a targeted therapy.
Main Methods:
- Comparative analysis of SMARCA4-inactivated cells versus MYC-activated cells regarding response to SAHA.
- Assessment of histone demethylase levels (KDM6A/UTX, KDM6B/JMJD3) in SMARCA4-mutant cells.
- In vivo studies using mouse models with orthotopically implanted SMARCA4-mutant lung cancer and SCCOHT cells treated with GSK-J4.
Main Results:
- SMARCA4-inactivated cells are refractory to SAHA, leading to H3K27me3 accumulation.
- SMARCA4-mutant cells exhibit impaired transactivation and reduced KDM6A/UTX and KDM6B/JMJD3 levels.
- Inhibition of KDM6 demethylases compromises cell viability in SMARCA4-mutant cells.
- GSK-J4 administration demonstrated significant anti-tumor effects in vivo.
Conclusions:
- SMARCA4-mutant cancers display a dependency on KDM6 histone demethylases.
- KDM6 inhibitors represent a promising therapeutic strategy for SMARCA4-deficient malignancies.
- Targeting KDM6 offers a novel approach for treating patients with SMARCA4-mutant cancers.
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