Potential Benefits of Using the Combination of Ibet with Ibtk Chronic Lymphocytic Leukemia and Other Tumor Types

Chronic lymphocytic leukemia (CLL) is characterized by clonal leukemia of mature B lymphocytes, being the most frequent leukemia in adults. B-cell receptor (BCR) down-regulation of the signaling pathway is believed to play a crucial role in cell survival and survival in CLL. The use of a BTK inhibitor (iBTK), e.g. ibrutinib, has shown high efficacy and low toxicity, but with frequent relapse in high-risk patients. Next generation sequencing identified genes associated with epigenetic regulation in CLL suggesting new therapeutic targets. The family of proteins with bromo-domains and extraterminal domains (BET) is composed of BRD2, BRD3, BRD4 and BRDT, which regulates expression of genes associated with growth and cell cycle, metabolism and tumor development. BET inhibitors (iBET) have shown promising results in studies, especially in acute leukemias. However, few studies have evaluated the role of antineoplastic iBET in CLL. Our objective was to evaluate the effect of iBET with iBTK combined treatment in ex vivo cells from patients with CLL and in other cell lines carrying ibrutinib target kinases. This is an observational and experimental study, in which we performed ex vivo functional (cell proliferation and death) and molecular (qPCR) assays with cells from CLL patients and cell lines (MOL13 and H1975). Our results demonstrated that the combination of IBTK (ibrutinib) with IBET (JQ1) induces apoptotic death in primary CLL cells and modulated genes that were essential in CLL development, such as IKZF3, TCL1A, BCL2 and MYC. We also demonstrated that the combination can inhibit proliferation, increasing apoptotic death and decreasing the expression of the MYC oncogene in the MOLM13 (acute myeloid leukemia cell line), in addition we identified that the H1975 (lung cancer cell line) had a significant reduction in proliferation with the combination of iBET with iBTK. According to this scenario, we conclude that the combination of iBET with iBTK seems to be a possible therapeutic strategy both in CLL and in other types of cancer, however, further analyses are needed.

No relevant conflicts of interest to declare.