Targetable leukaemia dependency on noncanonical PI3Kγ signalling

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Phosphoinositide-3-kinase-gamma (PI3Kγ) is known to affect anti-tumour immunity in solid cancers.
• The specific roles of PI3Kγ within cancer cells, particularly in leukaemias, remain largely unknown.

Purpose of the Study:

• To investigate the cell-intrinsic functions of PI3Kγ in acute leukaemias.
• To identify potential therapeutic targets within PI3Kγ signaling pathways for leukaemia treatment.

Main Methods:

• Genome-wide CRISPR interference screening was employed across various acute leukaemias.
• Functional analyses were conducted to understand PI3Kγ pathway activation and downstream effects.
• The study integrated genetic screening with biochemical and cellular assays.

Main Results:

• A subset of acute leukaemias exhibits a dependency on the PI3Kγ complex, linked to PIK3R5 activation and innate inflammatory signaling.
• PI3Kγ directly phosphorylates p21 (RAC1)-activated kinase 1 (PAK1), a key mediator of this dependency.
• Inhibition of PI3Kγ impairs mitochondrial oxidative phosphorylation by affecting PAK1 dephosphorylation.
• The PI3Kγ inhibitor eganelisib demonstrated efficacy in leukaemias with activated PIK3R5.
• Combination therapy with eganelisib and cytarabine improved survival in preclinical models, even with low PIK3R5 expression.

Conclusions:

• PI3Kγ-PAK1 signaling represents a targetable dependency in acute leukaemias.
• Targeting PI3Kγ, particularly with eganelisib, offers a potential therapeutic strategy for leukaemias.
• Combination therapies involving PI3Kγ inhibitors show enhanced efficacy and warrant clinical evaluation.