RRC ID 72489
Author Romero OA, Vilarrubi A, Alburquerque-Bejar JJ, Gomez A, Andrades A, Trastulli D, Pros E, Setien F, Verdura S, Farré L, Martín-Tejera JF, Llabata P, Oaknin A, Saigi M, Piulats JM, Matias-Guiu X, Medina PP, Vidal A, Villanueva A, Sanchez-Cespedes M.
Title SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade.
Journal Nat Commun
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.
Volume 12(1)
Pages 4319
Published 2021-7-14
DOI 10.1038/s41467-021-24618-3
PII 10.1038/s41467-021-24618-3
PMID 34262032
PMC PMC8280185
MeSH Animals Antineoplastic Agents / pharmacology Antineoplastic Agents / therapeutic use* Benzazepines / pharmacology Benzazepines / therapeutic use Cell Line, Tumor Cell Survival / drug effects DNA Helicases / deficiency* DNA Helicases / metabolism Drug Resistance, Neoplasm / drug effects Gene Expression Histone Deacetylase Inhibitors / pharmacology Histone Deacetylase Inhibitors / therapeutic use Histone Demethylases / antagonists & inhibitors* Histone Demethylases / genetics Histone Demethylases / metabolism Histones / metabolism Humans Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors* Jumonji Domain-Containing Histone Demethylases / genetics Jumonji Domain-Containing Histone Demethylases / metabolism Mice Neoplasms / drug therapy* Neoplasms / metabolism Nuclear Proteins / deficiency* Nuclear Proteins / metabolism Pyrimidines / pharmacology Pyrimidines / therapeutic use Transcription Factors / deficiency* Transcription Factors / metabolism Transcriptional Activation
IF 12.121
Human and Animal Cells Lu-165(RCB1184)