At a crossroads: how to translate the roles of PI3K in oncogenic and metabolic signalling into improvements in cancer therapy

Numerous agents targeting various phosphatidylinositol 3-kinase (PI3K) pathway components, including PI3K, AKT and mTOR, have been tested in oncology clinical trials, resulting in regulatory approvals for the treatment of selected patients with breast cancer, certain other solid tumours or particular haematological malignancies. However, given the prominence of PI3K signalling in cancer and the crucial role of this pathway in linking cancer growth with metabolism, these clinical results could arguably be improved upon. In this Review, we discuss past and present efforts to overcome the somewhat limited clinical efficacy of PI3Kα pathway inhibitors, including optimization of inhibitor specificity, patient selection and biomarkers across cancer types, with a focus on breast cancer, as well as identification and abrogation of signalling-related and metabolic mechanisms of resistance, and interventions to improve management of prohibitive adverse events. We highlight the advantages and limitations of laboratory-based model systems used to study the PI3K pathway, and propose technologies and experimental inquiries to guide the future clinical deployment of PI3K pathway inhibitors in the treatment of cancer. Several PI3K pathway inhibitors are currently approved as cancer treatments; however, finding an acceptable therapeutic window to target this key signalling cascade linking cancer growth with metabolism has proven challenging and the clinical results to date have arguably been disappointing. In this Review, Vasan and Cantley discuss the effects of PI3K pathway alterations on signalling and metabolism in solid tumours as well as past and present efforts to improve the somewhat limited clinical efficacy of PI3K pathway inhibitors, with a particular focus on PI3Kα in breast cancers.