PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting

Abstract

Oncogenic mutation of the phosphatidylinositol 3-kinase (PI3K) catalytic isoform p110α is frequent in human cancers, whereas the catalytic isoforms p110β, p110δ and p110γ are rarely mutated but can be overexpressed. Mutation or loss of expression of regulatory isoform p85α is also associated with cancer. Although class IA PI3K catalytic isoforms share structural and substrate similarities, they have specific roles in mediating PI3K signalling in different physiological and oncogenic contexts. Cancer cells with upregulation or mutation of receptor tyrosine kinases (RTKs), oncogenic RAS mutations or activating p110α mutations are highly dependent on p110α, even in the presence of mutation or loss of PTEN. In many cases, tumorigenesis that is driven by PTEN loss depends on p110β. However, PI3K isoform dependence in PTEN-deficient transformation may be governed by other PI3K isoforms that are dominant in a tissue or compartment, or shifted by coexisting oncogenic mutations. Isoforms p110α, p110δ and p110γ bind to and are activated by RAS subfamily GTPases, while p110β binds to and is activated by RHO subfamily GTPases RAC1 and CDC42. Non-isoform-selective pan-PI3K inhibitors have not yielded exciting clinical results, but second-generation PI3K drugs that target individual PI3K isoforms may be able to achieve greater therapeutic efficacy by offering improved specificity and reduced toxicity. The p110δ-selective inhibitor idelalisib has been remarkably effective in clinical trials for patients with B cell malignancies, while p110α-selective inhibitors have shown promise in early-phase trials for patients with solid tumours with PIK3CA mutations or HER2 amplification. Intrinsic and acquired resistance mechanisms are a continuing challenge for PI3K-directed therapeutic approaches. To overcome this, combination therapies and alternative dosing strategies are being developed and evaluated in both preclinical and clinical settings.