PI3K Inhibition (delta, gamma)

The phosphoinositide 3-kinase (PI3K) signaling pathway is a key regulator of cancer proliferation (rapid increase or spread) and metastasis (development of secondary growths away from a primary site of cancer). The PI3K pathway includes four Class I isoforms: alpha, beta, delta and gamma (α, β, δ, and γ). The four isoforms play unique roles in the survival of different tumor types with roles of some isoforms in the creation of supportive tumor microenvironments.

The Role of PI3K-d and PI3K-g in Hematologic Malignancies

PI3K-δ and PI3K-γ are primarily expressed in leukocytes such as B cells and T cells, where they have distinct and predominantly non-overlapping roles in key cellular functions, such as cell proliferation, cell differentiation, cell migration and activation.

PI3K signaling also has a significant role in supporting the growth and survival of many B-cell malignancies.2,5 PI3K activation is one direct consequence of B-cell receptor (BCR) activation, a critical survival signal for malignant B cells.6 Other key survival factors also transmit signals through PI3K isoforms2,5,7 reinforcing the dependence of certain B-cell malignancies on PI3K signaling.

In conditions like iNHL and CLL, neoplastic B cells rely on the support of non-neoplastic cells within their microenvironment. These support cells—including T cells, myeloid cells, and mesenchymal stromal cells—help sustain the proliferation and survival of malignant B cells.8

The signaling mediated by PI3K-δ and PI3K-γ provides complementary support to both the malignant B cell and the tumor microenvironment (TME). Accordingly, inhibition of PI3K-d and PI3K-g inhibits proliferation and survival of malignant B cells, reduces migration of key support cells into the TME, and enhances polarization of supportive macrophages from an immunosuppressive form (M2) to an anti-tumor phagocytic form (M1).9 A dual inhibitor of PI3K-δ,γ such as duvelisib may offer a more integrated approach to PI3K inhibition—one that may both disrupt intracellular PI3K signaling and help dismantle the malignant B-cell TME.