SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade
Por:
Romero, OA, Vilarrubi, A, Alburquerque-Bejar, JJ, Gomez, A, Andrades, A, Trastulli, D, Pros, E, Setien, F, Verdura, S, Farre, L, Martin-Tejera, JF, Llabata, P, Oaknin, A, Saigi, M, Piulats, JM, Matias-Guiu, X, Medina, PP, Vidal, A, Villanueva, A and Sanchez-Cespedes, M
Publicada:
14 jul 2021
Ahead of Print:
14 jul 2021
Resumen:
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. SMARCA4 is commonly inactivated in lung and ovarian cancers. Here the authors show that SMARCA4-deficient tumours have significantly reduced levels of the histone demethylases KDM6s and a strong dependency on these demethylases for tumour growth, so that they are vulnerable to KDM6s inhibition.
Filiaciones:
:
Josep Carreras Leukaemia Res Inst IJC, Canc Genet Grp, Barcelona, Spain
:
Josep Carreras Leukaemia Res Inst IJC, Canc Genet Grp, Barcelona, Spain
:
Josep Carreras Leukaemia Res Inst IJC, Canc Genet Grp, Barcelona, Spain
Gomez, A:
Vall dHebron Res Inst, Rheumatol Res Grp, Barcelona, Spain
Andrades, A:
Univ Granada, Fac Sci, Dept Biochem & Mol Biol 1, Granada, Spain
Univ Granada, Andalusian Reg Govt, Ctr Genom & Oncol Res Pfizer, GENYO, Granada, Spain
Trastulli, D:
Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Program PEBC, Genes & Canc Grp, Barcelona, Spain
Pros, E:
Josep Carreras Leukaemia Res Inst IJC, Canc Genet Grp, Barcelona, Spain
:
Josep Carreras Leukaemia Res Inst IJC, Canc Genet Grp, Barcelona, Spain
Verdura, S:
Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Program PEBC, Genes & Canc Grp, Barcelona, Spain
Farre, L:
Bellvitge Biomed Res Inst IDIBELL, Chemoresistance & Predict Factors Grp, Program Canc Therapeut Resistance ProCURE, Oncobell Program,Catalan Inst Oncol ICO, Barcelona, Spain
Martin-Tejera, JF:
Bellvitge Biomed Res Inst IDIBELL, Chemoresistance & Predict Factors Grp, Program Canc Therapeut Resistance ProCURE, Oncobell Program,Catalan Inst Oncol ICO, Barcelona, Spain
Llabata, P:
Josep Carreras Leukaemia Res Inst IJC, Canc Genet Grp, Barcelona, Spain
Oaknin, A:
Vall dHebron Hosp, Dept Med Oncol, Barcelona, Spain
:
Josep Carreras Leukaemia Res Inst IJC, Canc Genet Grp, Barcelona, Spain
Catalan Inst Oncol ICO, Dept Med Oncol, Barcelona, Spain
Piulats, JM:
Catalan Inst Oncol ICO, Dept Med Oncol, Barcelona, Spain
Matias-Guiu, X:
Univ Hosp Bellvitge, CIBERONC, IDIBELL, Dept Pathol, Barcelona, Spain
Medina, PP:
Univ Granada, Fac Sci, Dept Biochem & Mol Biol 1, Granada, Spain
Univ Granada, Andalusian Reg Govt, Ctr Genom & Oncol Res Pfizer, GENYO, Granada, Spain
Vidal, A:
Univ Hosp Bellvitge, CIBERONC, IDIBELL, Dept Pathol, Barcelona, Spain
Xenopat SL, Parc Cient Barcelona PCB, Barcelona, Spain
Villanueva, A:
Bellvitge Biomed Res Inst IDIBELL, Chemoresistance & Predict Factors Grp, Program Canc Therapeut Resistance ProCURE, Oncobell Program,Catalan Inst Oncol ICO, Barcelona, Spain
Xenopat SL, Parc Cient Barcelona PCB, Barcelona, Spain
:
Josep Carreras Leukaemia Res Inst IJC, Canc Genet Grp, Barcelona, Spain
Green Published, Green Submitted, gold
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