Noncanonical PI3Kγ signaling addiction is a therapeutic target in a subset of leukemias

Acute myeloid leukemia (AML) is a devastating disease with a median age of diagnosis of over 60 years. Thus, most AML patients are not eligible for intensive chemotherapy. Relapse remains common in patients with AML despite intensive therapy, which significantly compromises therapeutic options. Although several targeted therapies have been licensed for treating AML subsets bearing specific mutations and variant proteins essential for AML propagation, no actionable molecular targets are available for most AML patients. This has been hindered by disease heterogeneity and a general lack of effective biomarkers that could be used to predict cellular vulnerabilities to selected therapies for various AML subsets. A recent work published in Nature by Luo et al. identifies a phosphatidylinositol 3-kinase γ (PI3Kγ)-dependent therapeutic vulnerability in a subset of AML and provides a novel intervention strategy.

The PI3Ks are a family of heterodimeric lipid kinases consisting of a catalytic and an adaptor subunit. Mammals express three classes of PI3K enzymes (I, II, and III), and class I PI3Ks (PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ) convert phosphatidylinositol (4,5) bisphosphate to phosphatidylinositol (3,4,5) trisphosphate to activate signaling pathways implicated in cell proliferation, survival, and metabolism, whereas class II and class III PI3Ks are involved in membrane trafficking. The diverse functions of class I PI3Ks are controlled by four catalytic subunits (p110α, p110β, p110δ, and p110γ), which are encoded by PIK3CA, PIK3CB, PIK3CD, and PIK3CG, respectively. Class I PI3Ks are further classified into class IA (p110α, p110β, and p110δ) and class IB (p110γ) based on their distinct regulatory subunits. While class IA PI3Ks share a regulatory subunit of p85α/β, class IB p110γ binds to either a p101 or p87 subunit, encoded by PIK3R5 and PIK3R6, respectively.