SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade

• DOI: 10.1038/s41467-021-24618-3
• Publication Date: 2021-07-14T10:03:06Z
• Authors: Octavio A. Romero; Andrea Vilarrubi; Juan J. Alburquer...; Antonio Gomez; Alvaro Andrades; Deborah Trastulli; Eva Pros; Fernando Setien; Sara Verdura; Lourdes Farré; Juan F. Martín-Te...; Paula Llabata; Ana Oaknin; Maria Saigi; Josep M. Piulats; Xavier Matias-Guiu; Pedro P. Medina; August Vidal; Alberto Villanueva; Montse Sanchez-Ce...
• Keywords: SMARCA4

Abstract Despite the genetic inactivation of SMARCA4 , a core component SWI/SNF-complex commonly found in cancer, there are no therapies that effectively target SMARCA4-deficient tumours. Here, we show that, unlike cells with activated MYC oncogene, refractory to histone deacetylase inhibitor, SAHA, leading aberrant accumulation H3K27me3. -mutant also an impaired transactivation and significantly reduced levels demethylases KDM6A/UTX KDM6B/JMJD3, strong dependency on these demethylases, so its inhibition compromises cell viability. Administering KDM6 inhibitor GSK-J4 mice orthotopically implanted lung cancer or primary small carcinoma ovary, hypercalcaemic type (SCCOHT), had anti-tumour effects. In this work highlight vulnerability inhibitors as characteristic could be exploited for treating SMARCA4- mutant patients.