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  • Review Article
  • Published:

Development of PI3K inhibitors: lessons learned from early clinical trials

Nature Reviews Clinical Oncology volume 10, pages 143–153 (2013)Cite this article

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Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway has an important role in cell metabolism, growth, migration, survival and angiogenesis. Drug development aimed at targetable genetic aberrations in the PI3K/AKT/mTOR pathway has been fomented by observations that alterations in this pathway induce tumour formation and that inappropriate PI3K signalling is a frequent occurrence in human cancer. Many of the agents developed have been evaluated in early stage clinical trials. This Review focuses on early clinical and translational data related to inhibitors of the PI3K/AKT/mTOR pathway, as these data will likely guide the further clinical development of such agents. We review data from those trials, delineating the safety profile of the agents—whether observed sequelae could be mechanism-based or off-target effects—and drug efficacy. We describe predictive biomarkers explored in clinical trials and preclinical mechanisms of resistance. We also discuss key unresolved translational questions related to the clinical development of inhibitors of the PI3K/AKT/mTOR pathway and propose designs for biomarker-driven trials to address those issues.

Key Points

  • Agents targeting different components of the PI3K/AKT/mTOR pathway have been shown to be safe and well tolerated

  • These agents inhibit the PI3K/AKT/mTOR pathway at recommended doses, and are effective in multiple tumour types

  • No clear correlation among tumour type, genotype and sensitivity to inhibitors of the PI3K/AKT/mTOR pathway has emerged in initial clinical trials of second-generation inhibitors

  • Some unsolved questions in the late development of inhibitors of the PI3K/AKT/mTOR pathway might benefit from a systems biology approach and from biomarker-driven studies

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Figure 1: Signalling of the PI3K/AKT/mTOR pathway and relevant drugs that target each of the components of the pathway.
Figure 2: Distribution of ongoing clinical trials depending on the class of agent or treatment strategy.

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Acknowledgements

The authors acknowledge José Baselga, Lew Cantley, and other members of the “Stand Up to Cancer Dream Team” Translational Research Grant for sharing their insights on targeting PI3K. In addition, Joann Aaron (The University of Texas MD Anderson Cancer Center) for editing this manuscript.

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Authors and Affiliations

  1. Medical Oncology Department, Vall d'Hebrón University Hospital, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119, Edifici Maternoinfantil Planta 14, 08035, Barcelona, Spain

    Jordi Rodon & Josep Tabernero

  2. Vall d'Hebron Institute of Oncology, Passeig Vall d'Hebron 119, Edifici Maternoinfantil Planta 14, 08035, Barcelona, Spain

    Rodrigo Dienstmann & Violeta Serra

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  1. Jordi Rodon
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  2. Rodrigo Dienstmann
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  3. Violeta Serra
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  4. Josep Tabernero
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All the authors researched the data for the manuscript, made a substantial contribution to discussion of content, wrote and reviewed and edited the manuscript before submission.

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Correspondence to Jordi Rodon.

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Supplementary information

Supplementary Table 1

Development status of PI31/AKT/mTOR pathway inhibitors (DOC 132 kb)

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Rodon, J., Dienstmann, R., Serra, V. et al. Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol 10, 143–153 (2013). https://doi.org/10.1038/nrclinonc.2013.10

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