BET bromodomain inhibitor birabresib in mantle cell lymphoma: in vivo activity and identification of novel combinations to overcome adaptive resistance

The outcome of patients affected by mantle cell lymphoma (MCL) has improved in recent years, but there is still a need for novel treatment strategies for these patients. Human cancers, including MCL, present recurrent alterations in genes that encode transcription machinery proteins and of proteins involved in regulating chromatin structure, providing the rationale to pharmacologically target epigenetic proteins. The Bromodomain and Extra Terminal domain (BET) family proteins act as transcriptional regulators of key signalling pathways including those sustaining cell viability. Birabresib (MK-8628/OTX015) has shown anti-tumour activity in different preclinical models and has been the first BET inhibitor to successfully undergo early clinical trials. The activity of birabresib as a single agent and in combination, as well as its mechanism of action was studied in MCL cell lines. Birabresib showed in vitro and in vivo activities, which appeared mediated via downregulation of MYC targets, cell cycle and NFKB pathway genes and were independent of direct downregulation of CCND1. Additionally, the combination of birabresib with other targeted agents (especially pomalidomide, or inhibitors of BTK, mTOR and ATR) was beneficial in MCL cell lines. The authors concluded that the data provide the rationale to evaluate birabresib in patients affected by MCL.

Authors: Tarantelli C, Bernasconi E, Gaudio E, Cascione L, Restelli V, Arribas AJ, Spriano F, Rinaldi A, Mensah AA, Kwee I, Ponzoni M M.D, Zucca E, Carrassa L, Riveiro ME, Rezai K, Stathis A, Cvitkovic E, Bertoni F. ; Full Source: ESMO Open. 2018 Sep 26;3(6): e000387. doi: 10.1136/esmoopen-2018-000387. eCollection 2018.