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Clin Cancer Res. 2013 Nov 15;19(22):6183-92. doi: 10.1158/1078-0432.CCR-12-3904. Epub 2013 Sep 17.

Efficacy of BET bromodomain inhibition in Kras-mutant non-small cell lung cancer.

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Authors' Affiliations: Department of Molecular Pharmacology and Therapeutics, Oncology Research Institute, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois; Departments of Medical Oncology and Radiation Oncology; Belfer Institute for Applied Cancer Science; Ludwig Center at Dana-Farber/Harvard Cancer Center; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute; Department of Medicine, Brigham and Women's Hospital; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Departament de Fisiologia, Facultat de Farmàcia, Universitat de València, Valencia, Spain; and Department of Pediatrics, Columbia University Medical Center, New York, New York.



Amplification of MYC is one of the most common genetic alterations in lung cancer, contributing to a myriad of phenotypes associated with growth, invasion, and drug resistance. Murine genetics has established both the centrality of somatic alterations of Kras in lung cancer, as well as the dependency of mutant Kras tumors on MYC function. Unfortunately, drug-like small-molecule inhibitors of KRAS and MYC have yet to be realized. The recent discovery, in hematologic malignancies, that bromodomain and extra-terminal (BET) bromodomain inhibition impairs MYC expression and MYC transcriptional function established the rationale of targeting KRAS-driven non-small cell lung cancer (NSCLC) with BET inhibition.


We performed functional assays to evaluate the effects of JQ1 in genetically defined NSCLC cell lines harboring KRAS and/or LKB1 mutations. Furthermore, we evaluated JQ1 in transgenic mouse lung cancer models expressing mutant kras or concurrent mutant kras and lkb1. Effects of bromodomain inhibition on transcriptional pathways were explored and validated by expression analysis.


Although JQ1 is broadly active in NSCLC cells, activity of JQ1 in mutant KRAS NSCLC is abrogated by concurrent alteration or genetic knockdown of LKB1. In sensitive NSCLC models, JQ1 treatment results in the coordinate downregulation of the MYC-dependent transcriptional program. We found that JQ1 treatment produces significant tumor regression in mutant kras mice. As predicted, tumors from mutant kras and lkb1 mice did not respond to JQ1.


Bromodomain inhibition comprises a promising therapeutic strategy for KRAS-mutant NSCLC with wild-type LKB1, via inhibition of MYC function. Clinical studies of BET bromodomain inhibitors in aggressive NSCLC will be actively pursued. Clin Cancer Res; 19(22); 6183-92. ©2013 AACR.

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