Investigational BET bromodomain protein inhibitors in early stage clinical trials for acute myelogenous leukemia (AML).

1 a Hematology Department , Avicenne Hospital-Assistance Publique Hôpitaux de Paris (AP-HP), University Paris XIII , Bobigny , France. 2 b Laboratoire de Transfert des Leucémies , Institut Universitaire d'Hématologie, University Paris VII , Paris , France.

INTRODUCTION:

Acute myelogenous leukemia (AML) is a heterogeneous group of malignancies driven by genetic mutations and deregulated epigenetic control. Relapse/refractory disease remains frequent in younger patients and even more so in older patients, including treatment with epigenetic drugs in this age group, mainly with hypomethylating agents. New treatment strategies are urgently needed. The recent discovery that epigenetic readers of the bromodomain (BRD) and extraterminal (BET) protein family, are crucial for AML maintenance by transcription of oncogenic c-MYC lead to rapid development of BET inhibitors entering clinical trials. Areas covered: We provide a critical overview using main sources for the use of BET inhibitors in AML treatment. Limits of this treatment approach including resistance mechanisms and future directions including development of new generation BET inhibitors and combination strategies with other drugs are detailed. Expert opinion: BET inhibitors were expected to overcome limits of conventional treatment in patients as impressive in vitro data emerged recently in well-characterized AML subsets, including those associated with poor risk characteristics in the clinic. Nevertheless single activity of BET inhibitors appears to be modest and resistance mechanisms were already identified. BET inhibitors with alternative mechanisms of action and/or combination strategies with epigenetic drugs should be tested.

PMID: 28541716 DOI: 10.1080/13543784.2017.1335711