Many cancer types, like lung cancer or small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), bear mutations genetically inactivating SMARCA4 gene, a central component of the SWI/SNF chromatin remodeling complex, one of the main actors in the epigenetic control of gene expression.
A recent study, published in the prestigious journal Nature communications, reports a previously unknown association between the inactivation of the SMARCA4 gene with low levels of KDM6, a family of histone demethylases. This alone can explain why these tumors escape the anticancer activity of SAHA, a drug used in precision medicine targeting histone deacetylases. Being refractory to this drug, patients with tumors bearing inactivated SMARCA4 are left without this therapeutic option.
Results show that the dysregulation of the KDM6s impairs its epigenetic function and, in SMARCA4 deficient tumors, turn the cells hypersensitive to GSK-J4, a strong histone demethylase inhibitor. Upon treatment, only the cells in the tumor activate their internally programmed cell-death pathways -apoptosis or necrosis-, leading to significant reduction of the tumor, both in vitro and in animal models.
Andrea Vilarrubí and her supervisors, Dr. Sánchez-Céspedes and Dr. Romero, researchers at the Josep Carreras Leukaemia Research Institute, tested their hypothesis by using several cell line models, where they could deplete SMARCA4 in different contexts and see how cells responded to SAHA and GSK-J4. Colleagues from IDIBELL, VHIR, ICO and Granada University also participated in the study.
Their results were further validated by using orthotopic mouse models bearing human primary tumor derived directly from patients, the so called orthoxenografts, to test the therapeutic potential of the KDM6s inhibitors in a real physiological context. All animal experiments were approved by IDIBELL’s Ethical Committee.
The reported results will be of great value for the stratification of tumors according to their genetic or epigenetic background and foster the development of a precision medicine approach with high efficacy and low toxicity, using a new set of epigenetic modulators as anticancer drugs useful for the future treatment of lung and other epithelial cancers, like ovarian tumors.
Romero, O.A., Vilarrubi, A., Alburquerque-Bejar, J.J. et al. “SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade”. Nat Commun 12, 4319 (2021). https://doi.org/10.1038/s41467-021-24618-3