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

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

dc.contributor.author	Shimamura, Takeshi	es_ES
dc.contributor.author	Chen, Zhao	es_ES
dc.contributor.author	Soucheray, Margaret	es_ES
dc.contributor.author	Carretero, Julian	es_ES
dc.contributor.author	Kikuchi, Eiki	es_ES
dc.contributor.author	Tchaicha, Jeremy H.	es_ES
dc.contributor.author	Gao, Yandi	es_ES
dc.contributor.author	Cheng, Katherine A.	es_ES
dc.contributor.author	Cohoon, Travis J.	es_ES
dc.contributor.author	Qi, Jun	es_ES
dc.contributor.author	Akbay, Esra	es_ES
dc.contributor.author	Kimmelman, Alec C.	es_ES
dc.contributor.author	Kung, Andrew L.	es_ES
dc.contributor.author	Bradner, James E.	es_ES
dc.contributor.author	Wong, Kwok-Kin	es_ES
dc.date.accessioned	2015-06-19T07:47:46Z
dc.date.available	2015-06-19T07:47:46Z
dc.date.issued	2013	es_ES
dc.identifier.citation	Clinical cancer research : an official journal of the American Association for Cancer Research Vol. 19 Issue 22:	es_ES
dc.identifier.uri	http://hdl.handle.net/10550/44509
dc.description.abstract	PurposeAmplification 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 BET bromodomain inhibition impairs MYC expression and MYC transcriptional function established the rationale of targeting KRAS-driven NSCLC with BET inhibition.Experimental DesignWe performed functional assays to evaluate the effects of JQ1 in genetically defined NSCLC cells 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.ResultsWhile JQ1 is broadly active in NSCLC cells, activity of JQ1 in mutant KRAS NSCLC is abrogated by concurrent alteration or genetic knock-down 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.ConclusionBromodomain 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.	es_ES
dc.subject	LKB1	es_ES
dc.subject	KRAS	es_ES
dc.subject	NSCLC	es_ES
dc.subject	BET	es_ES
dc.subject	MYC	es_ES
dc.title	Efficacy of BET bromodomain inhibition in Kras-mutant non-small cell lung cancer	es_ES
dc.type	journal article	es_ES
dc.identifier.doi	10.1158/1078-0432.CCR-12-3904	es_ES
dc.identifier.idgrec	097155	es_ES