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首页> 外文期刊>Nature >Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer
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Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer

机译：三阴性乳腺癌对BET溴结构域抑制剂的反应和耐药

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摘要

Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy(1-3). BET bromodomain inhibitors, which have shown efficacy in several models of cancer(4-6), have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs(7-9). Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance.
机译：三阴性乳腺癌（TNBC）是一种异质性且在临床上具有侵略性的疾病，没有针对性的治疗方法（1-3）。 BET溴结构域抑制剂已在多种癌症模型中显示出疗效（4-6），但尚未在TNBC中进行评估。这些抑制剂通过与它们的乙酰赖氨酸识别模块竞争而取代了染色质的BET溴结构域蛋白，例如BRD4，从而抑制了致癌转录程序（7-9）。在这里，我们报告了TNBCs在体外和体内对BET溴结构域抑制的优先敏感性，为临床研究和进一步了解抗药性机制提供了依据。在为获得对先前敏感的TNBC的BET抑制的获得性抗性而选择的成对细胞系中，我们未能鉴定出网守突变，新的驱动事件或药物泵激活。耐BET的TNBC细胞仍然依赖于野生型BRD4，后者以与溴结构域无关的方式支持转录和细胞增殖。耐药TNBC的蛋白质组学研究确定与MED1密切相关，并归因于PP2A活性降低导致BRD4过度磷酸化，此处将其鉴定为主要的BRD4丝氨酸磷酸酶。总之，这些研究为TNBC中的BET抑制提供了理论依据，并提出了基于机制的联合策略以预测临床耐药性。

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  • 来源
    《Nature》 |2016年第7586期|413-417|共5页
  • 作者

    Shu Shaokun; Lin Charles Y.; He Housheng Hansen; Witwicki Robert M.; Tabassum Doris P.; Roberts Justin M.; Janiszewska Michalina; Huh Sung Jin; Liang Yi; Ryan Jeremy; Doherty Ernest; Mohammed Hisham; Guo Hao; Stover Daniel G.; Ekram Muhammad B.; Peluffo Guillermo; Brown Jonathan; DSantos Clive; Krop Ian E.; Dillon Deborah; McKeown Michael; Ott Christopher; Qi Jun; Ni Min; Rao Prakash K.; Duarte Melissa; Wu Shwu-Yuan; Chiang Cheng-Ming; Anders Lars; Young Richard A.; Winer Eric P.; Letai Antony; Barry William T.; Carroll Jason S.; Long Henry W.; Brown Myles; Liu X. Shirley; Meyer Clifford A.; Bradner James E.; Polyak Kornelia;

  • 作者单位

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA|Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA|Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 1L7, Canada|Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2M9, Canada;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA;

    Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 1L7, Canada;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Harvard Univ, Cambridge, MA 02138 USA;

    Univ Cambridge, Cambridge Inst, Canc Res UK, Cambridge CB2 0RE, England;

    Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA|Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA;

    Univ Cambridge, Cambridge Inst, Canc Res UK, Cambridge CB2 0RE, England;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA;

    Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA;

    Univ Texas SW Med Ctr Dallas, Simmons Comprehens Canc Ctr, Dept Biochem, Dallas, TX 75390 USA|Univ Texas SW Med Ctr Dallas, Simmons Comprehens Canc Ctr, Dept Pharmacol, Dallas, TX 75390 USA;

    Univ Texas SW Med Ctr Dallas, Simmons Comprehens Canc Ctr, Dept Biochem, Dallas, TX 75390 USA|Univ Texas SW Med Ctr Dallas, Simmons Comprehens Canc Ctr, Dept Pharmacol, Dallas, TX 75390 USA;

    Whitehead Inst Biomed Res, Cambridge, MA 02142 USA;

    Whitehead Inst Biomed Res, Cambridge, MA 02142 USA;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA;

    Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA|Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA;

    Univ Cambridge, Cambridge Inst, Canc Res UK, Cambridge CB2 0RE, England;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA|Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA;

    Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA|Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA|Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA|Broad Inst, Cambridge, MA 02142 USA;

    Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA|Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA|Broad Inst, Cambridge, MA 02142 USA;

    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA|Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA|Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA|Broad Inst, Cambridge, MA 02142 USA;

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