Inhibition of bromodomain and extra-terminal proteins increases sensitivity to venetoclax in chronic lymphocytic leukaemia.

Giovanna Carrà,Giuseppe Saglio,Antonio Cartellà,Paolo Nicoli,Beatrice Maffeo,Riccardo Taulli,Mara Brancaccio,Valentina Gaidano,Paola Circosta,Angelo Guerrasio,Alessandro Morotti,Marcello Francesco Lingua,Guido Parvis

doi:10.1111/jcmm.14857

Abstract

The development of drugs able to target BTK, PI3k‐delta and BCL2 has dramatically improved chronic lymphocytic leukaemia (CLL) therapies. However, drug resistance to these therapies has already been reported due to non‐recurrent changes in oncogenic pathways and genes expression signatures. In this study, we investigated the cooperative role of the BCL2 inhibitor venetoclax and the BRD4 inhibitor JQ1. In particular, we found that JQ1 shows additional activity with venetoclax, in CLL cell lines and in ex vivo isolated primary CD19+ lymphocytes, arguing in favour of combination strategies. Lastly, JQ1 is also effective in venetoclax‐resistant CLL cell lines. Together, our findings indicated that the BET inhibitor JQ1 could be a promising therapy in CLL, both as first‐line therapy in combination with venetoclax and as second‐line therapy, after the emergence of venetoclax‐resistant clones.

Highlights

The newest drugs to target chronic lymphocytic leukaemia (CLL) include the inhibitors of the intracellular B-cell receptor signalling (BCR inhibitor)[1] and the BCL2 inhibitor venetoclax.[2,3] B-cell receptor signalling inhibitors incorporate the direct BTK inhibitor ibrutinib and the inhibitor of PI3K-delta,[4] a BTK downstream effector, idelalisib
| 7 that (a) the BET inhibitor JQ1 has an anti-tumour effect in CLL; (b) the combinatorial treatment of venetoclax plus JQ1 highly improves the apoptotic effect of single treatments, both in cell lines and patient-derived models; (c) CLL cell line MEC-1 can develop resistance to venetoclax; (d) JQ1 is strongly efficacious as second-line strategy, in the case of emergence of venetoclaxresistant clones
While chemotherapy was historically designed as a poly-chemotherapy, where various agents target different mechanisms of cancer maintenance, new drugs were referred to the paradigm of the precision medicine due to high selectivity and precision

Summary

| INTRODUCTION

The newest drugs to target chronic lymphocytic leukaemia (CLL) include the inhibitors of the intracellular B-cell receptor signalling (BCR inhibitor)[1] and the BCL2 inhibitor venetoclax.[2,3] B-cell receptor signalling inhibitors incorporate the direct BTK inhibitor ibrutinib and the inhibitor of PI3K-delta,[4] a BTK downstream effector, idelalisib Both ibrutinib and idelalisib have entered the clinical field with impressive results in chemotherapy-refractory CLL patients. The major determinants are MCL-1 and BCLXL.[10,11] This means that, parallel to apoptosis promotion through BCL2 modulation, venetoclax affects the overall gene expression machinery Some of these genes may favour cells to survive. We have demonstrated the efficacy of BET inhibitors, JQ1, in combination with venetoclax and against venetoclax resistant clone

| EXPERIMENTAL PROCEDURES

Findings

| DISCUSSION