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Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary
Yibo Xue1,2, Brian Meehan3,4, Elizabeth Macdonald5,6
1Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6, Canada.
Abstract:
Inactivating mutations in SMARCA4 (BRG1), a key SWI/SNF chromatin remodelling gene, underlie small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). To reveal its druggable vulnerabilities, we perform kinase-focused RNAi screens and uncover that SMARCA4-deficient SCCOHT cells are highly sensitive to the inhibition of cyclin-dependent kinase 4/6 (CDK4/6). SMARCA4 loss causes profound downregulation of cyclin D1, which limits CDK4/6 kinase activity in SCCOHT cells and leads to in vitro and in vivo susceptibility to CDK4/6 inhibitors. SCCOHT patient tumors are deficient in cyclin D1 yet retain the retinoblastoma-proficient/p16INK4a-deficient profile associated with positive responses to CDK4/6 inhibitors. Thus, our findings indicate that CDK4/6 inhibitors, approved for a breast cancer subtype addicted to CDK4/6 activation, could be repurposed to treat SCCOHT. Moreover, our study suggests a novel paradigm whereby critically low oncogene levels, caused by loss of a driver tumor suppressor, may also be exploited therapeutically.
Insights
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is driven by SMARCA4 mutations. SCCOHT cells are sensitive to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, suggesting a new treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is characterized by inactivating mutations in the SMARCA4 gene.
- Understanding the molecular vulnerabilities of SCCOHT is crucial for developing targeted therapies.
Purpose of the Study:
- To identify druggable targets in SMARCA4-deficient SCCOHT.
- To investigate the potential of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors as a therapeutic strategy for SCCOHT.
Main Methods:
- Kinase-focused RNA interference (RNAi) screens were employed to identify drug sensitivities.
- Cellular and in vivo models of SCCOHT were used to assess drug efficacy.
- Analysis of cyclin D1 and retinoblastoma protein (Rb) pathway components in SCCOHT tumors.
Main Results:
- SMARCA4-deficient SCCOHT cells exhibit high sensitivity to CDK4/6 inhibition.
- SMARCA4 loss leads to decreased cyclin D1 levels, sensitizing cells to CDK4/6 inhibitors.
- SCCOHT tumors show a cyclin D1-deficient, retinoblastoma-proficient profile, indicative of potential response to CDK4/6 inhibitors.
Conclusions:
- CDK4/6 inhibitors represent a promising therapeutic option for SCCOHT and could be repurposed from breast cancer treatment.
- The study highlights a novel therapeutic approach targeting critically low oncogene levels resulting from tumor suppressor loss.
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