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.
PIK3CA is one of the most frequently mutated genes in cancer; the PI3K pathway is altered in a large number of cancer types, driving cell signalling, growth and metabolism, and PI3K inhibitors have been in development for over four decades.
Seven drugs that target the PI3K pathway have received regular or accelerated approval from the FDA, including alpelisib in combination with fulvestrant for advanced-stage, PIK3CA-mutant, oestrogen receptor-positive breast cancer. AKT inhibitors and next-generation mTOR inhibitors are currently being tested in early phase and late-phase clinical trials.
Adaptive signalling, epigenetic and metabolic changes in cancer cells can limit the clinical efficacy of PI3K inhibitors. In addition, PI3K inhibition in non-cancer cells causes hyperglycaemia and other on-target adverse effects that limit patient tolerability, as well as hyperinsulinaemia, which can lead to reactivation of cancer cells; the net effect of these alterations is attenuation of PI3K inhibitor efficacy.
Targeting insulin signalling, improved management of hyperglycaemia, development of mutant-specific PI3K inhibitors, and validation of refined biomarkers of response and resistance are novel translational strategies currently being tested to improve the therapeutic window of PI3K inhibitors in patients with cancer.
Genomic, transcriptomic, proteomic, phosphoproteomic and metabolomic analyses of patients with PIK3CA-mutant tumours receiving PI3K inhibitors are needed to discover new pathways for combination therapies in different cancer types.
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The authors wish to acknowledge the many seminal papers on this subject that they could not discuss and cite owing to space and editorial limits. The authors acknowledge support from the NIH (grants K08 CA245192 to N.V. and R35 CA197588 to L.C.C.) and the Susan G. Komen Breast Cancer Foundation (to N.V.).
N.V. reports consulting activities for Novartis and is on the scientific advisory board of Heligenics. L.C.C. is a founder, shareholder and member of the scientific advisory board of Agios Pharmaceuticals, a co-founder and shareholder of Faeth Therapeutics, and a founder and former member of the scientific advisory board of Ravenna Pharmaceuticals (previously Petra Pharmaceuticals); these companies are all developing therapies for cancer. L.C.C. has also received research funding from Ravenna Pharmaceuticals.
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Vasan, N., Cantley, L.C. At a crossroads: how to translate the roles of PI3K in oncogenic and metabolic signalling into improvements in cancer therapy. Nat Rev Clin Oncol 19, 471–485 (2022). https://doi.org/10.1038/s41571-022-00633-1
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