OTX015 (MK-8628), a novel BET inhibitor, exhibits antitumor activity in non-small cell and small cell lung cancer models harboring different oncogenic mutations

Oncotarget. 2016 Dec 20;7(51):84675-84687. doi: 10.18632/oncotarget.13181.


Inhibitors targeting epigenetic control points of oncogenes offer a potential mean of blocking tumor progression in small cell and non-small cell lung carcinomas (SCLC, NSCLC). OTX015 (MK-8628) is a BET inhibitor selectively blocking BRD2/3/4. OTX015 was evaluated in a panel of NSCLC or SCLC models harboring different oncogenic mutations. Cell proliferation inhibition and cell cycle arrest were seen in sensitive NSCLC cells. MYC and MYCN were downregulated at both the mRNA and protein levels. In addition, OTX015-treatment significantly downregulated various stemness cell markers, including NANOG, Musashi-1, CD113 and EpCAM in H3122-tumors in vivo. Conversely, in SCLC models, weak antitumor activity was observed with OTX015, both in vitro and in vivo. No predictive biomarkers of OTX015 activity were identified in a large panel of candidate genes known to be affected by BET inhibition. In NSCLC models, OTX015 was equally active in both EML4-ALK positive and negative cell lines, whereas in SCLC models the presence of functional RB1 protein, which controls cell progression at G1, may be related to the final biological outcome of OTX015. Gene expression profiling in NSCLC and SCLC cell lines showed that OTX015 affects important genes and pathways with a very high overlapping between both sensitive and resistant cell lines. These data support the rationale for the OTX015 Phase Ib (NCT02259114) in solid tumors, where NSCLC patients with rearranged ALK gene or KRAS-positive mutations are currently being treated.

Keywords: KRAS; NSCLC; OTX015 (MK-8628); SCLC; bromodomain.

Publication types

  • Comparative Study

MeSH terms

  • Acetanilides / pharmacology*
  • Anaplastic Lymphoma Kinase
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Cell Cycle Checkpoints
  • Cell Line, Tumor
  • Cell Proliferation
  • Female
  • Gene Expression Regulation
  • Heterocyclic Compounds, 3-Ring / pharmacology*
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Mice
  • Mice, Nude
  • Mutation / genetics
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / genetics
  • Small Cell Lung Carcinoma / drug therapy*
  • Small Cell Lung Carcinoma / genetics
  • Transcription Factors
  • Xenograft Model Antitumor Assays


  • Acetanilides
  • Antineoplastic Agents
  • BRD2 protein, human
  • Heterocyclic Compounds, 3-Ring
  • OTX015
  • Transcription Factors
  • ALK protein, human
  • Alk protein, mouse
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases