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

Takeshi Shimamura, Zhao Chen, Margaret Soucheray, Julian Carretero, Eiki Kikuchi, Jeremy H. Tchaicha, Yandi Gao, Katherine A. Cheng, Travis J. Cohoon, Jun Qi, Esra Akbay, Alec C. Kimmelman, Andrew L. Kung, James E. Bradner, Kwok Kin Wong

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Abstract

Purpose: 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. Experimental Design: 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. Results: 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)6183-6192
Number of pages10
JournalClinical Cancer Research
Volume19
Issue number22
DOIs
StatePublished - Nov 15 2013

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Non-Small Cell Lung Carcinoma
Lung Neoplasms
Neoplasms
Hematologic Neoplasms
Drug Resistance
Transgenic Mice
Research Design
Down-Regulation
Phenotype
Cell Line
Mutation
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Shimamura, T., Chen, Z., Soucheray, M., Carretero, J., Kikuchi, E., Tchaicha, J. H., ... Wong, K. K. (2013). Efficacy of BET bromodomain inhibition in KRAS-mutant non-small cell lung cancer. Clinical Cancer Research, 19(22), 6183-6192. https://doi.org/10.1158/1078-0432.CCR-12-3904

Efficacy of BET bromodomain inhibition in KRAS-mutant non-small cell lung cancer. / Shimamura, Takeshi; Chen, Zhao; Soucheray, Margaret; Carretero, Julian; Kikuchi, Eiki; Tchaicha, Jeremy H.; Gao, Yandi; Cheng, Katherine A.; Cohoon, Travis J.; Qi, Jun; Akbay, Esra; Kimmelman, Alec C.; Kung, Andrew L.; Bradner, James E.; Wong, Kwok Kin.

In: Clinical Cancer Research, Vol. 19, No. 22, 15.11.2013, p. 6183-6192.

Research output: Contribution to journalArticle

Shimamura, T, Chen, Z, Soucheray, M, Carretero, J, Kikuchi, E, Tchaicha, JH, Gao, Y, Cheng, KA, Cohoon, TJ, Qi, J, Akbay, E, Kimmelman, AC, Kung, AL, Bradner, JE & Wong, KK 2013, 'Efficacy of BET bromodomain inhibition in KRAS-mutant non-small cell lung cancer', Clinical Cancer Research, vol. 19, no. 22, pp. 6183-6192. https://doi.org/10.1158/1078-0432.CCR-12-3904
Shimamura T, Chen Z, Soucheray M, Carretero J, Kikuchi E, Tchaicha JH et al. Efficacy of BET bromodomain inhibition in KRAS-mutant non-small cell lung cancer. Clinical Cancer Research. 2013 Nov 15;19(22):6183-6192. https://doi.org/10.1158/1078-0432.CCR-12-3904
Shimamura, Takeshi ; Chen, Zhao ; Soucheray, Margaret ; Carretero, Julian ; Kikuchi, Eiki ; Tchaicha, Jeremy H. ; Gao, Yandi ; Cheng, Katherine A. ; Cohoon, Travis J. ; Qi, Jun ; Akbay, Esra ; Kimmelman, Alec C. ; Kung, Andrew L. ; Bradner, James E. ; Wong, Kwok Kin. / Efficacy of BET bromodomain inhibition in KRAS-mutant non-small cell lung cancer. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 22. pp. 6183-6192.
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AU - Tchaicha, Jeremy H.

AU - Gao, Yandi

AU - Cheng, Katherine A.

AU - Cohoon, Travis J.

AU - Qi, Jun

AU - Akbay, Esra

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AU - Kung, Andrew L.

AU - Bradner, James E.

AU - Wong, Kwok Kin

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