PI3K and cancer: lessons, challenges and opportunities
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Updated: May 3, 2026
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Published on: September 5, 2018
David A Fruman1, Christian Rommel2
1Department of Molecular Biology & Biochemistry, and Institute for Immunology, University of California, Irvine, 3242 McGaugh Hall, Irvine, California 92697, USA.
Abstract:
The central role of phosphoinositide 3-kinase (PI3K) activation in tumour cell biology has prompted a sizeable effort to target PI3K and/or downstream kinases such as AKT and mammalian target of rapamycin (mTOR) in cancer. However, emerging clinical data show limited single-agent activity of inhibitors targeting PI3K, AKT or mTOR at tolerated doses. One exception is the response to PI3Kδ inhibitors in chronic lymphocytic leukaemia, where a combination of cell-intrinsic and -extrinsic activities drive efficacy. Here, we review key challenges and opportunities for the clinical development of inhibitors targeting the PI3K-AKT-mTOR pathway. Through a greater focus on patient selection, increased understanding of immune modulation and strategic application of rational combinations, it should be possible to realize the potential of this promising class of targeted anticancer agents.
Insights
Targeting the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway in cancer shows limited success. Improved patient selection and combination therapies may unlock the potential of these targeted agents.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- The PI3K-AKT-mTOR pathway is crucial in tumor cell biology.
- Inhibitors targeting PI3K, AKT, or mTOR show limited single-agent efficacy in clinical trials.
- Chronic lymphocytic leukemia demonstrates an exception with PI3Kδ inhibitors.
Purpose of the Study:
- To review challenges and opportunities in developing PI3K-AKT-mTOR pathway inhibitors for cancer.
- To explore strategies for enhancing the clinical utility of these targeted agents.
Main Methods:
- Literature review of clinical data on PI3K-AKT-mTOR pathway inhibitors.
- Analysis of factors influencing drug response and resistance.
- Examination of immune modulation and combination therapy approaches.
Main Results:
- Single-agent activity of PI3K, AKT, or mTOR inhibitors is generally limited at tolerated doses.
- PI3Kδ inhibitors show efficacy in chronic lymphocytic leukemia due to combined intrinsic and extrinsic activities.
- Challenges in clinical development include patient selection and understanding complex pathway interactions.
Conclusions:
- Realizing the potential of PI3K-AKT-mTOR inhibitors requires a focus on patient stratification.
- Understanding the pathway's role in immune modulation is critical for effective combination strategies.
- Rational combination therapies hold promise for improving outcomes with these targeted anticancer agents.
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