Targeting BET Bromodomain Proteins in Solid Tumors

Overview

Journal Oncotarget

Specialty Oncology

Date 2016 Jun 11

PMID 27283767

Citations 59

Authors

Vaibhav Sahai

Amanda J Redig

Katharine A Collier

Frank D Eckerdt

Hidayatullah G Munshi

Affiliations

Soon will be listed here.

Abstract

There is increasing interest in inhibitors targeting BET (bromodomain and extra-terminal) proteins because of the association between this family of proteins and cancer progression. BET inhibitors were initially shown to have efficacy in hematologic malignancies; however, a number of studies have now shown that BET inhibitors can also block progression of non-hematologic malignancies. In this Review, we summarize the efficacy of BET inhibitors in select solid tumors; evaluate the role of BET proteins in mediating resistance to current targeted therapies; and consider potential toxicities of BET inhibitors. We also evaluate recently characterized mechanisms of resistance to BET inhibitors; summarize ongoing clinical trials with these inhibitors; and discuss potential future roles of BET inhibitors in patients with solid tumors.

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References

Roy N, Malik S, Villanueva K, Urano A, Lu X, von Figura G . Brg1 promotes both tumor-suppressive and oncogenic activities at distinct stages of pancreatic cancer formation. Genes Dev. 2015; 29(6):658-71. PMC: 4378197. DOI: 10.1101/gad.256628.114. View

Carethers J, Jung B . Genetics and Genetic Biomarkers in Sporadic Colorectal Cancer. Gastroenterology. 2015; 149(5):1177-1190.e3. PMC: 4589489. DOI: 10.1053/j.gastro.2015.06.047. View

Baselga J, Campone M, Piccart M, Burris 3rd H, Rugo H, Sahmoud T . Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2011; 366(6):520-9. PMC: 5705195. DOI: 10.1056/NEJMoa1109653. View

French C, Ramirez C, Kolmakova J, Hickman T, Cameron M, Thyne M . BRD-NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene. 2007; 27(15):2237-42. DOI: 10.1038/sj.onc.1210852. View

Zou Z, Huang B, Wu X, Zhang H, Qi J, Bradner J . Brd4 maintains constitutively active NF-κB in cancer cells by binding to acetylated RelA. Oncogene. 2013; 33(18):2395-404. PMC: 3913736. DOI: 10.1038/onc.2013.179. View

Yauch R, Dijkgraaf G, Alicke B, Januario T, Ahn C, Holcomb T . Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science. 2009; 326(5952):572-4. PMC: 5310713. DOI: 10.1126/science.1179386. View

Llovet J, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J . Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008; 359(4):378-90. DOI: 10.1056/NEJMoa0708857. View

Grayson A, Walsh E, Cameron M, Godec J, Ashworth T, Ambrose J . MYC, a downstream target of BRD-NUT, is necessary and sufficient for the blockade of differentiation in NUT midline carcinoma. Oncogene. 2013; 33(13):1736-1742. PMC: 3942361. DOI: 10.1038/onc.2013.126. View

Fukuda A, Wang S, Morris 4th J, Folias A, Liou A, Kim G . Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell. 2011; 19(4):441-55. PMC: 3075548. DOI: 10.1016/j.ccr.2011.03.002. View

10.

Ryan D, Hong T, Bardeesy N . Pancreatic adenocarcinoma. N Engl J Med. 2014; 371(11):1039-49. DOI: 10.1056/NEJMra1404198. View

11.

Cloughesy T, Cavenee W, Mischel P . Glioblastoma: from molecular pathology to targeted treatment. Annu Rev Pathol. 2013; 9:1-25. DOI: 10.1146/annurev-pathol-011110-130324. View

12.

Govindan R, Ding L, Griffith M, Subramanian J, Dees N, Kanchi K . Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell. 2012; 150(6):1121-34. PMC: 3656590. DOI: 10.1016/j.cell.2012.08.024. View

13.

Fedele M, Battista S, Kenyon L, Baldassarre G, Fidanza V, Klein-Szanto A . Overexpression of the HMGA2 gene in transgenic mice leads to the onset of pituitary adenomas. Oncogene. 2002; 21(20):3190-8. DOI: 10.1038/sj.onc.1205428. View

14.

Delmore J, Issa G, Lemieux M, Rahl P, Shi J, Jacobs H . BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011; 146(6):904-17. PMC: 3187920. DOI: 10.1016/j.cell.2011.08.017. View

15.

Briscoe J, Therond P . The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol. 2013; 14(7):416-29. DOI: 10.1038/nrm3598. View

16.

Rudin C, Hann C, Laterra J, Yauch R, Callahan C, Fu L . Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med. 2009; 361(12):1173-8. PMC: 5317279. DOI: 10.1056/NEJMoa0902903. View

17.

Rathert P, Roth M, Neumann T, Muerdter F, Roe J, Muhar M . Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. Nature. 2015; 525(7570):543-547. PMC: 4921058. DOI: 10.1038/nature14898. View

18.

Tang Y, Gholamin S, Schubert S, Willardson M, Lee A, Bandopadhayay P . Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition. Nat Med. 2014; 20(7):732-40. PMC: 4108909. DOI: 10.1038/nm.3613. View

19.

Puissant A, Frumm S, Alexe G, Bassil C, Qi J, Chanthery Y . Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013; 3(3):308-23. PMC: 3672953. DOI: 10.1158/2159-8290.CD-12-0418. View

20.

Ross-Innes C, Stark R, Teschendorff A, Holmes K, Ali H, Dunning M . Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature. 2012; 481(7381):389-93. PMC: 3272464. DOI: 10.1038/nature10730. View