Genetic modifiers of the BRD4-NUT dependency of NUT midline carcinoma uncovers a synergism between BETis and CDK4/6is

被引：52

作者：

Liao, Sida ^{[1
,2
]}

Maertens, Ophelia ^{[1
,3
,4
]}

Cichowski, Karen ^{[1
,3
,4
]}

Elledge, Stephen J. ^{[1
,2
,4
]}

机构：

[1] Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA

[2] Harvard Med Sch, Howard Hughes Med Inst, Dept Genet, Program Virol, Boston, MA 02115 USA

[3] Harvard Med Sch, Boston, MA 02115 USA

[4] Harvard Med Sch, Ludwig Ctr Harvard, Boston, MA 02215 USA

来源：

GENES & DEVELOPMENT | 2018年 / 32卷 / 17-18期

基金：

美国国家卫生研究院;

关键词：

BETi; BRD4; CDK4; genetic screens; JQ1; oncogenes; tumor suppressor; HUMAN CANCER GENES; BREAST-CANCER; BROMODOMAIN INHIBITORS; SIGNALING PATHWAYS; CELL-CYCLE; C-MYC; ANEUPLOIDY PATTERNS; PROTEIN-DEGRADATION; EXPRESSION ANALYSIS; COLORECTAL-CANCER;

D O I：

10.1101/gad.315648.118

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Bromodomain and extraterminal (BET) domain inhibitors (BETis) show efficacy on NUT midline carcinoma (NMC). However, not all NMC patients respond, and responders eventually develop resistance and relapse. Using CRISPR and ORF expression screens, we systematically examined the ability of cancer drivers to mediate resistance of NMC to BETis and uncovered six general classes/pathways mediating resistance. Among these, we showed that RRAS2 attenuated the effect of JQ1 in part by sustaining ERK pathway function during BRD4 inhibition. Furthermore, overexpression of Kruppel-like factor 4 (KLF4), mediated BETi resistance in NMC cells through restoration of the E2F and MYC gene expression program. Finally, we found that expression of cyclin D1 or an oncogenic cyclin D3 mutant or RB1 loss protected NMC cells from BETi-induced cell cycle arrest. Consistent with these findings, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors showed synergistic effects with BETis on NMC in vitro as well as in vivo, thereby establishing a potential two-drug therapy for NMC.

引用

页码：1188 / 1200

页数：13

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