Revival of PI3K inhibitors in non-Hodgkin’s lymphoma

The phosphoinositide 3-kinase (PI3K) family is classified into three distinct classes (I, II and III). Class I is most relevant to cell growth and survival and has been the target for drug development of cancer. The class I PI3K pathway includes four isoforms: α, β, δ, and γ [1]. PI3Kδ and -γ expression is largely limited to leukocytes, while PI3K-α and -β are ubiquitously expressed [2]. PI3Kα mutations and amplifications have been identified across multiple cancer subtypes and both overexpression of PI3Kα and gain of function PI3Kα mutations were found to be oncogenic [3–6]. PI3Kα is also the primary isoform required for insulin signaling [7]. PI3Kβ isoform has roles in regulating formation and stability of integrin which is required for platelet activation [8]. PI3Kδ and -γ regulate leukocyte trafficking and cell proliferation [9–12]. Mice with functionally deficient PI3Kδ have impaired immune systems with abnormal antibody development and inflammatory bowel disease [12]. However, dissecting the individual function of class I PI3K isoforms have been complicated by the heterodimeric nature of the proteins as altering expression of one subunit affects the expression profile of others.

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