Genetic requirement for Mycl and efficacy of RNA Pol I inhibition in mouse models of small cell lung cancer

被引：78

作者：

Kim, Dong-Wook ^{[1
]}

Wu, Nan ^{[2
,3
]}

Kim, Young-Chul ^{[4
]}

Cheng, Pei Feng ^{[5
]}

Basom, Ryan ^{[6
]}

Kim, Dongkyoon ^{[7
]}

Dunn, Colin T. ^{[1
]}

Lee, Anastasia Y. ^{[1
]}

Kim, Keebeom ^{[1
]}

Lee, Chang Sup ^{[1
]}

Singh, Andrew ^{[1
]}

Gazdar, Adi F. ^{[8
,9
,10
]}

Harris, Chris R. ^{[11
,12
,13
]}

Eisenman, Robert N. ^{[5
]}

Park, Kwon-Sik ^{[1
]}

MacPherson, David ^{[2
,3
]}

机构：

[1] Univ Virginia, Sch Med, Dept Microbiol Immunol & Canc Biol, Charlottesville, VA 22908 USA

[2] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA

[3] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA

[4] H Lee Moffitt Canc Ctr & Res Inst, Dept Biostat & Bioinformat, Tampa, FL 33612 USA

[5] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA

[6] Fred Hutchinson Canc Res Ctr, Genom & Bioinformat Shared Resource, Seattle, WA 98109 USA

[7] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Palo Alto, CA 94305 USA

[8] Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA

[9] Univ Texas SW Med Ctr Dallas, Simmons Canc Ctr, Dallas, TX 75390 USA

[10] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA

[11] Raymond & Beverly Sackler Fdn, New Brunswick, NJ 08901 USA

[12] Rutgers Canc Inst New Jersey, New Brunswick, NJ 08903 USA

[13] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Pediat, New Brunswick, NJ 08901 USA

来源：

GENES & DEVELOPMENT | 2016年 / 30卷 / 11期

关键词：

oncogene; progression; neuroendocrine; transcription factor; ribosome biogenesis; COMBINATION THERAPY; RIBOSOME BIOGENESIS; POLYMERASE-I; INACTIVATION; ACTIVATION; TRP53; MAX; RB1; DNA;

D O I：

10.1101/gad.279307.116

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Small cell lung cancer (SCLC) is a devastating neuroendocrine carcinoma. MYCL (L-Myc) is frequently amplified in human SCLC, but its roles in SCLC progression are poorly understood. We isolated preneoplastic neuroendocrine cells from a mouse model of SCLC and found that ectopic expression of L-Myc, c-Myc, or N-Myc conferred tumor-forming capacity. We focused on L-Myc, which promoted pre-rRNA synthesis and transcriptional programs associated with ribosomal biogenesis. Deletion of Mycl in two genetically engineered models of SCLC resulted in strong suppression of SCLC. The high degree of suppression suggested that L-Myc may constitute a therapeutic target for a broad subset of SCLC. We then used an RNA polymerase I inhibitor to target rRNA synthesis in an autochthonous Rb/p53-deleted mouse SCLC model and found significant tumor inhibition. These data reveal that activation of RNA polymerase I by L-Myc and other MYC family proteins provides an axis of vulnerability for this recalcitrant cancer.

引用

页码：1289 / 1299

页数：11

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