BET-bromodomain proteins ‘read’ acetylated lysine residues on histone tails to modulate transcription. Bromodoman inhibitors (BRDi) are an emerging class of anti-cancer agents with selective toxicity against MYC-driven malignancies.1 2 Although BRDi downregulate oncogenic MYC transcription in certain cellular contexts, precise mechanism of apoptosis induction and the role of non-MYC targets in tumour responses remain undefined.
The Eμ-Myc model of aggressive ‘Burkitt-like’ lymphoma has been extensively used for preclinical investigations characterising MYC-mediated lymphomagenesis and responses to novel therapeutics. We utilised Eμ-Myc lymphomas on informative genetic backgrounds to investigate mechanisms of apoptosis induction by the prototypical BRDi, JQ1.
JQ1 demonstrated potent pro-apoptotic activity at ‘on target’ concentrations (IC50 250-500nM at 24 hrs) that was p53-independent, but abrogated in tumors with constitutively active RAS or overexpression of BCL2. In contrast to prior reports in human MYC–translocated cell lines, JQ1 did not downregulate MYC transcription. However Myc protein became hypophosphorylated at sites downstream of RAS, MAPK and PI3K signaling pathways and subsequently degraded. Consistent with this observation, resistance to JQ1 in RAS mutant tumours was overcome by co-treatment with the PI3K inhibitor, BEZ235. JQ1 treatment of mice bearing transplanted Eμ-Myc lymphomas resulted in significant prolongation of survival associated with a decreased rate of disease progression as indicated by peripheral blood leukocytosis and bioluminescence imaging.
Our data suggests post-transcriptional mechanisms of MYC downregulation in response to BRDi may be mediated by an interaction with pro-survival PI3K/MAPK signaling. Further in vivo evaluation of the efficacy of JQ1 in combination with PI3K or MAPK pathway inhibitors is warranted, particularly in the context of activated RAS.