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

Octavio A. Romero (), Andrea Vilarrubi, Juan J. Alburquerque-Bejar, Antonio Gomez, Alvaro Andrades, Deborah Trastulli, Eva Pros, Fernando Setien, Sara Verdura, Lourdes Farré, Juan F. Martín-Tejera, Paula Llabata, Ana Oaknin, Maria Saigi, Josep M. Piulats, Xavier Matias-Guiu, Pedro P. Medina, August Vidal, Alberto Villanueva and Montse Sanchez-Cespedes ()
Additional contact information
Octavio A. Romero: Josep Carreras Leukaemia Research Institute (IJC), Badalona
Andrea Vilarrubi: Josep Carreras Leukaemia Research Institute (IJC), Badalona
Juan J. Alburquerque-Bejar: Josep Carreras Leukaemia Research Institute (IJC), Badalona
Antonio Gomez: Vall d’Hebron Research Institute
Alvaro Andrades: University of Granada
Deborah Trastulli: Bellvitge Biomedical Research Institute-IDIBELL Barcelona
Eva Pros: Josep Carreras Leukaemia Research Institute (IJC), Badalona
Fernando Setien: Josep Carreras Leukaemia Research Institute (IJC), Badalona
Sara Verdura: Bellvitge Biomedical Research Institute-IDIBELL Barcelona
Lourdes Farré: L’Hospitalet del Llobregat
Juan F. Martín-Tejera: L’Hospitalet del Llobregat
Paula Llabata: Josep Carreras Leukaemia Research Institute (IJC), Badalona
Ana Oaknin: Vall d’Hebrón Hospital
Maria Saigi: Josep Carreras Leukaemia Research Institute (IJC), Badalona
Josep M. Piulats: Catalan Institute of Oncology (ICO)
Xavier Matias-Guiu: L’Hospitalet del Llobregat
Pedro P. Medina: University of Granada
August Vidal: L’Hospitalet del Llobregat
Alberto Villanueva: L’Hospitalet del Llobregat
Montse Sanchez-Cespedes: Josep Carreras Leukaemia Research Institute (IJC), Badalona

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24618-3

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DOI: 10.1038/s41467-021-24618-3

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