RT Journal Article
T1 SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade.
A1 Romero, Octavio A
A1 Vilarrubi, Andrea
A1 Alburquerque-Bejar, Juan J
A1 Gomez, Antonio
A1 Andrades, Alvaro
A1 Trastulli, Deborah
A1 Pros, Eva
A1 Setien, Fernando
A1 Verdura, Sara
A1 Farré, Lourdes
A1 Martín-Tejera, Juan F
A1 Llabata, Paula
A1 Oaknin, Ana
A1 Saigi, Maria
A1 Piulats, Josep M
A1 Matias-Guiu, Xavier
A1 Medina, Pedro P
A1 Vidal, August
A1 Villanueva, Alberto
A1 Sanchez-Cespedes, Montse
AB 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.
YR 2021
FD 2021-07-14
LK http://hdl.handle.net/10668/18200
UL http://hdl.handle.net/10668/18200
LA en
DS RISalud
RD Apr 11, 2025