The next-generation BET inhibitor, PLX51107, delays melanoma growth in a CD8-mediated manner

Pigment Cell Melanoma Res. 2019 Sep;32(5):687-696. doi: 10.1111/pcmr.12788. Epub 2019 May 20.


Epigenetic agents such as bromodomain and extra-terminal region inhibitors (BETi) slow tumor growth via tumor intrinsic alterations; however, their effects on antitumor immunity remain unclear. A recent advance is the development of next-generation BETi that are potent and display a favorable half-life. Here, we tested the BETi, PLX51107, for immune-based effects on tumor growth in BRAF V600E melanoma syngeneic models. PLX51107 delayed melanoma tumor growth and increased activated, proliferating, and functional CD8+ T cells in tumors leading to CD8+ T-cell-mediated tumor growth delay. PLX51107 decreased Cox2 expression, increased dendritic cells, and lowered PD-L1, FasL, and IDO-1 expression in the tumor microenvironment. Importantly, PLX51107 delayed the growth of tumors that progressed on anti-PD-1 therapy; a response associated with decreased Cox2 levels, decreased PD-L1 expression on non-immune cells, and increased intratumoral CD8+ T cells. Thus, next-generation BETi represent a potential first-line and secondary treatment strategy for metastatic melanoma by eliciting effects, at least in part, on antitumor CD8+ T cells.

Keywords: BET inhibitor; Cox2; T cells; anti-PD-1 non-responsive; melanoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Proliferation
  • Humans
  • Male
  • Melanoma / drug therapy*
  • Melanoma / immunology
  • Melanoma / pathology
  • Mice
  • Mice, Inbred C57BL
  • Oxazoles / pharmacology*
  • Oxazoles / therapeutic use
  • Proteins / antagonists & inhibitors*
  • Pyridines / pharmacology*
  • Pyridines / therapeutic use
  • Pyrroles / pharmacology*
  • Pyrroles / therapeutic use
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Oxazoles
  • Proteins
  • Pyridines
  • Pyrroles
  • bromodomain and extra-terminal domain protein, human
  • PLX51107