Efficacy and Mechanism of Action of the Novel Bromodomain Inhibitor, PLX51107, in B Cell Malignancies

BRD4 functions as an important epigenetic regulator of transcription of pathways involved in oncogenesis. While down regulation of c-myc following BRD4 inhibition has been described, the exact mechanism of action of BRD4 inhibitors across B cell malignancies remains unclear. We demonstrate the in vitro efficacy of PLX51107 across a spectrum of B cell lymphoma (BCL) cell lines and the signaling pathways involved. PLX51107 demonstrated potent anti-tumor effects (median IC50 of 300 NM), primarily driven by cell cycle arrest and induction of premature senescence. Treatment of BCL cultures resulted in down regulation of c-myc, p-IRAK, and P-MAPK Erk 1/ 2. PLX51107 affected the expression of proteins in several critical cellular pathways in sensitive cell lines, while proteins involved in drug resistance were affected in resistant cell lines. These results demonstrate that PLX51107 has mechanisms of action beyond down regulation of the c-myc transcriptional program and is a promising targeted therapeutic agent.

Author(s): Monica Mead, Erika Von Euw, Dylan Conklin, Kanthinh Manivong, Eileen Do, Dennis J Slamon and Sarah Larson

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