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Review
. 2015 Aug:23:98-107.
doi: 10.1016/j.coph.2015.05.016. Epub 2015 Jun 25.

Drugging PI3K in cancer: refining targets and therapeutic strategies

Timothy A Yap  1 , Lynn Bjerke  2 , Paul A Clarke  3 , Paul Workman  4
Affiliations
Review

Drugging PI3K in cancer: refining targets and therapeutic strategies

Timothy A Yap et al. Curr Opin Pharmacol. 2015 Aug.

Abstract

The phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated pathogenic signalling routes in human cancers, making it a rational and important target for innovative anticancer drug development and precision medicine. The three main classes of PI3K inhibitors currently in clinical testing comprise dual pan-Class I PI3K/mTOR inhibitors, pan-Class I PI3K inhibitors lacking significant mTOR activity and isoform-selective PI3K inhibitors. A major step forward in recent years is the progression of over 30 small molecule PI3K inhibitors into clinical trials and the first regulatory approval of the PI3Kδ inhibitor idelalisib for multiple B-cell malignancies. This review article focuses on the progress made in the discovery and development of novel PI3K inhibitors, with an emphasis on antitumour activity and tolerability profiles for agents that have entered clinical trials. We also discuss the key issues of drug resistance, patient selection approaches and rational targeted combinations. Finally, we envision the future development and use of PI3K inhibitors for the treatment of patients with a range of malignancies.

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Figures

Figure 1
Figure 1
The PI3K pathway with respective PI3K inhibitors. When PI3K is activated, phosphatidylinositol 3,4,5-trisphosphate (PIP3) is generated from phosphatidylinositol 3,4-bisphosphate (PIP2), and recruits AKT to the cell membrane [80, 81]. This leads to a conformational change and phosphorylation of AKT and its subsequent activation. AKT then translocates to the cytoplasm and nucleus, where phosphorylation of various downstream substrates involved in the regulation of multiple cellular functions, including proliferation, survival and growth occurs. The PI3K pathway is one of the most frequently activated signalling pathways in human cancers, affecting 30–50% of tumours, making it a rational target for novel anticancer drug development. The red arrows indicate the respective mechanisms of action of different PI3K inhibitors, which include the dual PI3K/mTOR inhibitors, pan-Class I PI3K inhibitors and isoform-selective PI3K inhibitors. Individual examples of different PI3K inhibitors in clinical testing are shown in the figure. The table in the figure lists the regulatory and catalytic subunits of the respective PI3K classes.
Figure 2
Figure 2
Chemical structures of PI3K inhibitors highlighted in this article.
See this image and copyright information in PMC

References

    1. Workman P., Clarke P.A., Guillard S., Raynaud F.I. Drugging the PI3 kinome. Nat Biotechnol. 2006;24:794–796. - PubMed
    1. Clarke P.A., Workman P. Phosphatidylinositide-3-kinase inhibitors: addressing questions of isoform selectivity and pharmacodynamic/predictive biomarkers in early clinical trials. J Clin Oncol. 2012;30:331–333. - PubMed
    1. Klempner S.J., Myers A.P., Cantley L.C. What a tangled web we weave: emerging resistance mechanisms to inhibition of the phosphoinositide 3-kinase pathway. Cancer Discov. 2013;3:1345–1354. - PMC - PubMed

    2. Excellent article on resistance mechanisms to PI3K pathway inhibitors.

    1. Sanger Institute Cosmic database. http://www.sanger.ac.uk/genetics/CGP/cosmic/.
    1. Samuels Y., Wang Z., Bardelli A., Silliman N., Ptak J., Szabo S., Yan H., Gazdar A., Powell S.M., Riggins G.J. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554. - PubMed

    2. First study to demonstrate PIK3CA mutations in human cancer.

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