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

Abstract

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. However, both drugs are less effective with p53 mutated/deleted CLL cells. This type of CLL remains highly challenging form which should better benefit from the treatment with the BCL2 inhibitor, venetoclax, which acts as a pro-apoptotic trigger. 5 With such a remarkable option of drugs and the possibility to target p53 mutated/deleted clones, CLL should be considered as an easily treatable cancer and the intent to eradicate the disease no longer a fleeting mirage. Unfortunately, cases of resistance to each of these novel drugs have already been reported and mechanisms of resistance deeply investigated. 2,6-8 Interestingly, however, no recurrent abnormalities or mutations have been associated with a specific pattern of resistance, posing some concerns on how resistant patients can be further treated. AbstractThe 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.

High expression level of ROR1 and ROR1-signaling associates with venetoclax resistance in chronic lymphocytic leukemia

“…Similarly, we found that MEC1 or MEC1-ROR1 cells transfected to express high levels of BCL2 WT , BCL2 A113P , or BCL2 G101V also had reduced sensitivity to venetoclax compared to the parent MEC1 or MEC1-ROR1 cells. Despite the noted resistance of MEC1 cells to venetoclax [ 45 ], we still found that MEC1-ROR1 were even less sensitive to this drug, indicating that the expression of ROR1 per se can enhance drug resistance.…”

“…MEC1 leukemia cells already are relatively resistant to venetoclax compared to the primary leukemia cells of patients with CLL [ 45 ]. Nonetheless, we examined whether the expression of ROR1 could enhance the resistance of this cell line to venetoclax in vitro.…”

Co-Operativity between MYC and BCL-2 Pro-Survival Proteins in Cancer

“…Indeed, a wide range of BETi have now been tested together with various BH3-mimetics, though most studies have focussed on Venetoclax where enhanced responses from combining the drugs have been seen in vitro and in vivo in many haematological malignancies including T cell lymphoma, CLL, T cell acute lymphoblastic leukaemia, and diffuse large B cell lymphoma [ 289 , 290 , 291 , 292 , 293 , 294 , 295 , 296 , 297 ], and some solid tumours such as small cell lung cancer [ 298 ]. The dual BCL-XL/BCL-2 inhibitor Navitoclax was also shown to synergise with BETi in small cell lung cancer, colorectal cancer, glioma and B-cell lymphomas [ 299 , 300 , 301 , 302 ], whilst BH3-mimetics targeting MCL-1 enhance BETi activity in AML and melanoma [ 292 , 303 ].…”

A novel triple-action inhibitor targeting B-cell receptor signaling and BRD4 demonstrates preclinical activity in chronic lymphocytic leukemia

“…Despite the remarkable preclinical activity of BET inhibitors in hematological malignancies, studies to identify beneficial combination therapy approaches to enhance efficacy have been reported [31]. As expected, synergism was observed when combining BET inhibitors (e.g., BAY 1238097, GS-5829, OTX015) with inhibitors of BTK (ibrutinib), SYK (entospletinib), PI3K (copanlisib, idelalisib), or BCL2 (venetoclax) in preclinical models of CLL [32][33][34] and DLBCL-RT [35]. Interestingly, the anti-leukemic activity of BET inhibitor, GS-5829, proved to be synergistic in combination with ibrutinib or idelalisib in primary CLL / nurse-like cell co-cultures reflective of the LN TME in CLL [32].…”