SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade
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Romero, O.A... [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]
SponsorshipSpanish 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
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.