MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition

被引：425

作者：

Mollaoglu, Gurkan ^{[1
]}

Guthrie, Matthew R. ^{[1
]}

Boehm, Stefanie ^{[2
,3
]}

Braegelmann, Johannes ^{[2
,3
]}

Can, Ismail ^{[1
]}

Ballieu, Paul M. ^{[1
]}

Marx, Annika ^{[2
,3
]}

George, Julie ^{[3
]}

Heinen, Christine ^{[3
]}

Chalishazar, Milind D. ^{[1
]}

Cheng, Haixia ^{[1
]}

Ireland, Abbie S. ^{[1
]}

Denning, Kendall E. ^{[1
]}

Mukhopadhyay, Anandaroop ^{[1
]}

Vahrenkamp, Jeffery M. ^{[1
]}

Berrett, Kristofer C. ^{[1
]}

Mosbruger, Timothy L. ^{[4
]}

Wang, Jun ^{[5
]}

Kohan, Jessica L. ^{[6
,7
]}

Salama, Mohamed E. ^{[6
,7
]}

Witt, Benjamin L. ^{[6
,7
]}

Peifer, Martin ^{[3
,8
]}

Thomas, Roman K. ^{[3
,9
,10
]}

Gertz, Jason ^{[1
]}

Johnson, Jane E. ^{[11
]}

Gazdar, Adi F. ^{[12
]}

Wechsler-Reya, Robert J.

Sos, Martin L. ^{[2
,3
]}

Oliver, Trudy G. ^{[1
]}

机构：

[1] Univ Utah, Huntsman Canc Inst, Dept Oncol Sci, Salt Lake City, UT 84112 USA

[2] Univ Cologne, Inst Pathol, Fac Med, Mol Pathol, D-50937 Cologne, Germany

[3] Univ Cologne, Fac Med, Dept Translat Genom, Ctr Integrated Oncol Cologne Bonn, D-50931 Cologne, Germany

[4] Huntsman Canc Inst, Bioinformat Shared Resource, Salt Lake City, UT 84112 USA

[5] Sanford Burnham Prebys Med Discovery Inst, Tumor Initiat & Maintenance Program, La Jolla, CA 92037 USA

[6] Univ Utah, Dept Pathol, Salt Lake City, UT 84112 USA

[7] ARUP Labs, Salt Lake City, UT 84112 USA

[8] Univ Cologne, Ctr Mol Med Cologne, D-50931 Cologne, Germany

[9] Univ Hosp Cologne, Dept Pathol, D-50937 Cologne, Germany

[10] German Canc Consortium DKTK, German Canc Res Ctr DKFZ, D-69120 Heidelberg, Germany

[11] Univ Texas Southwestern Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA

[12] UT Southwestern Med Ctr, Dept Pathol, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75235 USA

来源：

CANCER CELL | 2017年 / 31卷 / 02期

关键词：

MOUSE MODEL; N-MYC; TUMOR; LINES; CARCINOMAS; FAMILY; GENE; IDENTIFICATION; HETEROGENEITY; AMPLIFICATION;

D O I：

10.1016/j.ccell.2016.12.005

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Loss of the tumor suppressors RB1 and TP53 and MYC amplification are frequent oncogenic events in small cell lung cancer (SCLC). We show that Myc expression cooperates with Rb1 and Trp53 loss in the mouse lung to promote aggressive, highly metastatic tumors, that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low "variant" subset of SCLC with high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which, combined with chemotherapy, strongly suppresses tumor progression and increases survival. These data identify molecular features for patient stratification and uncover a potential targeted treatment approach for MYC-driven SCLC.

引用

页码：270 / 285

页数：16

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