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

Authors :: Romero, Octavio A.
Vilarrubi, Andrea
Alburquerque-Béjar, Juan Jos
Gómez Moruno, Antonio
Andrades, Álvaro
Trastulli, Deborah
Pros, Eva
Setien, Fernando
Verdura, Sara
Farre, Lourdes
Martín-Tejera, Juan F.
Llabata, Paula
Oaknin, Ana
Saigi, María
Piulats, Josep M.
Matias-Guiu, Xavier
Medina, Pedro P.
Vidal, August
Villanueva, Alberto
Sanchez-Cespedes, Montse
Universitat Autònoma de Barcelona
Institut Català de la Salut
[Romero OA, Vilarrubi A, Alburquerque-Bejar JJ] Cancer Genetics Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Spain. [Gomez A] Grup de Recerca en Reumatologia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Andrades A] Department of Biochemistry and Molecular Biology I. Faculty of Sciences, University of Granada, Granada, Spain. GENYO. Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Regional Government, Granada, Spain. [Trastulli D] Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute-IDIBELL Barcelona, Barcelona, Spain. [Oaknin A] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain
Vall d'Hebron Barcelona Hospital Campus
Source :: Nature Communications, Dipòsit Digital de la UB, Universidad de Barcelona, Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021), Digibug. Repositorio Institucional de la Universidad de Granada, instname, Scientia, r-IGTP. Repositorio Institucional de Producción Científica del Instituto de Investigación Germans Trias i Pujol
Publication Year :: 2021
Publisher :: Nature Publishing Group UK, 2021.
Abstract: The authors thank Isabel Bartolessis (Cancer Genetics Group) at IJC for technical assistance. This work was supported by the Spanish Ministry of Economy and CompetitivityMINECO (grant number SAF-2017-82186R, to M.S.-C., and grant PI19/01320 to A. Villanueva) and from the Fundacion Cientifica of the Asociacion Espanola Contra el Cancer (AECC) (grant number GCB14142170MONT) to M.S.-C. A. Villanueva is also funded by the Department of Health of the Generalitat de Catalunya (2014SGR364). O.A. R. received a Juan de la Cierva postdoctoral contract (grant No. IJCI-2016-28201, until November 2019) and an AECC research contract (INVES19045ROME from December 2019). A. Vilarrubi, P.L. and A.A. are supported by pre-doctoral contracts from the Spanish MINECO (FPI-fellowship: PRE2018-084624, BES-2015-072204 and FPU17/00067). M.S. was supported by a Rio Hortega contract from the Instituto de Salud Carlos III (CM17/00180). L.F. received a European Union Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Actions grant agreement, number 799850. 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. Spanish Ministry of Economy and Competitivity-MINECO SAF-2017-82186R PI19/01320 Fundacion Cientifica of the Asociacion Espanola Contra el Cancer (AECC) GCB14142170MONT Department of Health of the Generalitat de Catalunya 2014SGR364 Juan de la Cierva postdoctoral contract IJCI-2016-28201 AECC research contract INVES19045ROME Spanish MINECO PRE2018-084624 BES-2015-072204 FPU17/00067 Instituto de Salud Carlos III European Commission CM17/00180 European Union Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Actions grant agreement 799850