HDAC3 is critical in tumor development and therapeutic resistance in Kras-mutant non-small cell lung cancer.
HDAC3 is critical in tumor development and therapeutic resistance in Kras-mutant non-small cell lung cancer.
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DOI：
10.1126/sciadv.add3243
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发表时间：
2023-03-15
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
--
作者：
HDAC3是组蛋白去乙酰化酶（HDAC）抑制剂在临床发展中作为癌症治疗的主要靶点之一，但HDAC3在实体瘤中的体内作用尚不清楚。我们确定了HDAC3在kras突变肺癌中的关键作用。通过基因工程小鼠模型（GEMMs），我们发现HDAC3是体内肺肿瘤生长所必需的。研究发现，HDAC3可指导和增强肺癌谱系转录因子NKX2-1的转录作用，介导一组常见靶基因的表达。我们发现FGFR1是HDAC3的一个关键靶点。利用这一点，我们发现，当Kras/ lkb1突变细胞对MEK抑制剂trametinib产生耐药性时，HDAC3依赖性转录盒变得过度激活，这可以通过HDAC1/HDAC3抑制剂entinostat治疗逆转。我们发现，在Kras/LKB1 GEMM中，恩替他加曲美替尼联合治疗可获得治疗益处。在基因工程小鼠模型中，HDAC3对Kras、lkb1依赖性肺肿瘤生长和治疗耐药至关重要。
HDAC3 is one of the main targets of histone deacetylase (HDAC) inhibitors in clinical development as cancer therapies, yet the in vivo role of HDAC3 in solid tumors is unknown. We identified a critical role for HDAC3 in Kras-mutant lung cancer. Using genetically engineered mouse models (GEMMs), we found that HDAC3 is required for lung tumor growth in vivo. HDAC3 was found to direct and enhance the transcription effects of the lung cancer lineage transcription factor NKX2-1 to mediate expression of a common set of target genes. We identified FGFR1 as a critical previously unidentified target of HDAC3. Leveraging this, we identified that an HDAC3-dependent transcriptional cassette becomes hyperactivated as Kras/LKB1-mutant cells develop resistance to the MEK inhibitor trametinib, and this can be reversed by treatment with the HDAC1/HDAC3 inhibitor entinostat. We found that the combination of entinostat plus trametinib treatment elicits therapeutic benefit in the Kras/LKB1 GEMM. HDAC3 is essential for Kras, Lkb1-dependent lung tumor growth and therapeutic resistance in genetic engineered mouse models.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
23.9
作者：
Dost AFM;Moye AL;Vedaie M;Tran LM;Fung E;Heinze D;Villacorta-Martin C;Huang J;Hekman R;Kwan JH;Blum BC;Louie SM;Rowbotham SP;Sainz de Aja J;Piper ME;Bhetariya PJ;Bronson RT;Emili A;Mostoslavsky G;Fishbein GA;Wallace WD;Krysan K;Dubinett SM;Yanagawa J;Kotton DN;Kim CF
通讯作者：
Kim CF
DOI：
10.1042/bcj20200502
发表时间：
2021-04-16
期刊：
The Biochemical journal
影响因子：
--
作者：
Darling NJ;Cohen P
通讯作者：
Cohen P
影响因子：
64.8
作者：
De Raedt, Thomas;Beert, Eline;Cichowski, Karen
通讯作者：
Cichowski, Karen