Pharmacological targeting of PI3K isoforms as a therapeutic strategy in chronic lymphocytic leukaemia

• Inhibition of PI3K may still be effective in CLL patients resistant to ibrutinib.
• Functional redundancy between PI3K isoforms may be a mechanism of drug resistance.
• Targeting multiple PI3K isoforms can increase cytotoxicity against CLL cells.

PI3Kδ inhibitors such as idelalisib are providing improved therapeutic options for the treatment of chronic lymphocytic leukaemia (CLL). However under certain conditions, inhibition of a single PI3K isoform can be compensated by the other PI3K isoforms, therefore PI3K inhibitors which target multiple PI3K isoforms may provide greater efficacy. The development of compounds targeting multiple PI3K isoforms (α, β, δ, and γ) in CLL cells, in vitro, resulted in sustained inhibition of BCR signalling but with enhanced cytotoxicity and the potential for improve clinical responses. This review summarises the progress of PI3K inhibitor development and describes the rationale and potential for targeting multiple PI3K isoforms.