| Literature DB >> 28089889 |
Gurkan Mollaoglu1, Matthew R Guthrie1, Stefanie Böhm2, Johannes Brägelmann2, Ismail Can1, Paul M Ballieu1, Annika Marx2, Julie George3, Christine Heinen3, Milind D Chalishazar1, Haixia Cheng1, Abbie S Ireland1, Kendall E Denning1, Anandaroop Mukhopadhyay1, Jeffery M Vahrenkamp1, Kristofer C Berrett1, Timothy L Mosbruger4, Jun Wang5, Jessica L Kohan6, Mohamed E Salama6, Benjamin L Witt6, Martin Peifer7, Roman K Thomas8, Jason Gertz1, Jane E Johnson9, Adi F Gazdar10, Robert J Wechsler-Reya5, Martin L Sos11, Trudy G Oliver12.
Abstract
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.Entities:
Keywords: ASCL1; Aurora kinase inhibitor; MYC; NEUROD1; chemotherapy; genetically engineered mouse model; neuroendocrine; small-cell lung cancer
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Year: 2017 PMID： 28089889 PMCID： PMC5310991 DOI： 10.1016/j.ccell.2016.12.005
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743