This month in Blood, Arianna Bottoni from the Ohio State University, Columbus, Ohio, and colleagues published a study in which they sought to elucidate the mechanisms by which the Bruton’s Tyrosine Kinase (BTK) is overexpressed in CLL, which is thought to lead to ibrutinib resistance, and discover potential therapeutic targets. BTK is a key molecule in the signaling pathway, which results in cell survival and proliferation of cells via PLCγ2, ERK, and Akt. Ibrutinib acts by covalently binding to BTK, resulting in irreversible inhibition and a decrease in pro-survival and proliferative signaling.
Post-ibrutinib CLL relapse has been associated with a mutation in BTK which is thought to result in ibrutinib no longer irreversibly inhibiting BTK and instead modifying the interaction to make it reversible. These kinds of relapses and progression during ibrutinib treatment are associated with poorer outcome, underlining the need to better understand ibrutinib resistance and finds ways of preventing resistance or new ways to treat CLL.
MicroRNAs are small pieces of double stranded RNA, which can modulate post-transcriptional expression of genes, and ultimately proteins. Histone Deacetylases (HDACs) are molecules, which act on DNA and can silence gene expression. In CLL, HDACs are known to silence the expression of certain microRNAs.
- In primary CLL cells, BTK is a direct target of some microRNAs
- miR-425 and miR-210 were found to be expressed at lower levels in primary CLL cells
- miR-425 and miR-210 were found to strongly reduce BTK protein expression
- Hypothesized that epigenetic HDAC inhibition of microRNAs is involved with ibrutinib resistance in CLL via increasing BTK expression
- Both in vitro and in a mouse CLL model (Eμ-TCL-1), combination of ibrutinib and a HDAC inhibitor was found to result in a superior BTK inhibitory response
In summary, the authors identified a novel potential therapeutic strategy for treating mutant BTK-based ibrutinib-resistant CLL through use of HDAC inhibitors, which relieve the epigenetic silencing of specific microRNAs and in-turn target and inhibit BTK protein expression. The authors state that, as HDAC inhibitors are not well tolerated in CLL patients, a potential strategy may involve using HDAC inhibitors in combination with ibrutinib after detection of molecular relapse (increased C481S-BTK mutant copies) in order to maintain for as long as possible the sensitivity to ibrutinib. The authors also state that this data may be applicable to other types of ibrutinib-resistant lymphomas, however due to the growing need for a treatment for ibrutinib-resistant CLL, clinical trials may be warranted.