Resistance to Epigenetic-Targeted Therapy Engenders Tumor Cell Vulnerabilities Associated with Enhancer Remodeling

被引：66

作者：

Iniguez, Amanda Balboni ^{[1
,2
,3
]}

Alexe, Gabriela ^{[1
,2
,3
,4
]}

Wang, Emily Jue ^{[1
,2
,3
]}

Roti, Giovanni ^{[1
,2
,3
,5
]}

Pate, Sarvagna ^{[1
,2
,6
]}

Chen, Liying ^{[1
,2
,3
]}

Kitara, Samuel ^{[1
,2
,3
]}

Conway, Amy ^{[1
,2
]}

Robichaud, Amanda L. ^{[1
,2
]}

Stolte, Bjoern ^{[1
,2
,3
,7
]}

Bandopadhayay, Pratiti ^{[1
,2
,3
]}

Goodale, Amy ^{[3
]}

Pantel, Sasha ^{[3
]}

Lee, Yenarae ^{[3
]}

Cheff, Dorian M. ^{[8
]}

Hall, Matthew D. ^{[8
]}

Guha, Rajarshi ^{[8
]}

Davis, Mindy, I ^{[8
]}

Menard, Marie ^{[9
,10
,11
,12
]}

Nasholm, Nicole ^{[9
,10
,11
,12
]}

Weiss, William A. ^{[9
,10
,11
,12
]}

Qi, Jun ^{[13
]}

Beroukhim, Rameen ^{[3
,14
,15
]}

Piccioni, Federica ^{[3
]}

Johannessen, Cory ^{[3
]}

Stegmaier, Kimberly ^{[1
,2
,3
]}

机构：

[1] Harvard Med Sch, Dept Pediat Oncol, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA

[2] Harvard Med Sch, Boston Childrens Hosp, 450 Brookline Ave, Boston, MA 02215 USA

[3] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[4] Boston Univ, Bioinformat Grad Program, Boston, MA 02215 USA

[5] Univ Parma, Dept Med & Surg, Hematol & BMT, Parma, Italy

[6] Harvard MIT Program Hlth Sci & Technol, Cambridge, MA 02139 USA

[7] Ludwig Maximilians Univ Munchen, Univ Hosp, Dr von Hauner Childrens Hosp, Dept Pediat, D-80337 Munich, Germany

[8] NIH, Natl Ctr Advancing Translat Sci, Bethesda, MD 20892 USA

[9] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA

[10] Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA 94158 USA

[11] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94158 USA

[12] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA

[13] Dana Farber Canc Inst, Div Canc Biol, Boston, MA 02215 USA

[14] Harvard Med Sch, Dept Med, Boston, MA 02215 USA

[15] Dana Farber Canc Inst, Div Med Oncol, Boston, MA 02215 USA

来源：

CANCER CELL | 2018年 / 34卷 / 06期

关键词：

BET BROMODOMAIN INHIBITORS; SELECTIVE-INHIBITION; NEUROBLASTOMA; CANCER; TRANSCRIPTION; LEUKEMIA; MYCN; HETEROGENEITY; ALIGNMENT; PLATFORM;

D O I：

10.1016/j.ccell.2018.11.005

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Drug resistance represents a major challenge to achieving durable responses to cancer therapeutics. Resistance mechanisms to epigenetically targeted drugs remain largely unexplored. We used bromodomain and extra-terminal domain (BET) inhibition in neuroblastoma as a prototype to model resistance to chromatin modulatory therapeutics. Genome-scale, pooled lentiviral open reading frame (ORF) and CRISPR knockout rescue screens nominated the phosphatidylinositol 3-kinase (PI3K) pathway as promoting resistance to BET inhibition. Transcriptomic and chromatin profiling of resistant cells revealed that global enhancer remodeling is associated with upregulation of receptor tyrosine kinases (RTKs), activation of PI3K signaling, and vulnerability to RTK/PI3K inhibition. Large-scale combinatorial screening with BET inhibitors identified PI3K inhibitors among the most synergistic upfront combinations. These studies provide a roadmap to elucidate resistance to epigenetic-targeted therapeutics and inform efficacious combination therapies.

引用

页码：922 / +

页数：24

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