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Development and safety of PI3K inhibitors in cancer
Miaomiao Yu1, Jiajia Chen1, Zhifei Xu1
1Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Zijingang Campus, Hangzhou, 310058, Zhejiang, People's Republic of China.
Abstract:
The phosphatidylinositol 3-kinase (PI3K) signalling pathway regulates cell survival, proliferation, migration, metabolism and other vital cellular life processes. In addition, activation of the PI3K signalling pathway is important for cancer development. As a result, a variety of PI3K inhibitors have been clinically developed to treat malignancies. Although several PI3K inhibitors have received approval from the Food and Drug Administration (FDA) for significant antitumour activity, frequent and severe adverse effects have greatly limited their clinical application. These toxicities are mostly on-target and immune-mediated; nevertheless, the underlying mechanisms are still unclear. Current management usually involves intervention through symptomatic treatment, with discontinuation if toxicity persists. Therefore, it is necessary to comprehensively understand these adverse events and ensure the clinical safety application of PI3K inhibitors by establishing the most effective management guidelines, appropriate intermittent dosing regimens and new combination administration. Here, the focus is on the development of PI3K inhibitors in cancer therapy, with particular emphasis on isoform-specific PI3K inhibitors. The most common adverse effects of PI3K inhibitors are also covered, as well as potential mechanisms and management approaches.
Insights
Phosphatidylinositol 3-kinase (PI3K) inhibitors show promise in cancer therapy but cause severe side effects. Understanding these toxicities is crucial for developing better management strategies and safer clinical applications.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- The phosphatidylinositol 3-kinase (PI3K) pathway is crucial for cell functions and implicated in cancer development.
- PI3K inhibitors are FDA-approved for cancer treatment, demonstrating antitumor activity.
- Despite efficacy, severe on-target, immune-mediated toxicities limit clinical use of PI3K inhibitors.
Purpose of the Study:
- To review the development of PI3K inhibitors in cancer therapy, focusing on isoform-specific agents.
- To discuss common adverse effects associated with PI3K inhibitors.
- To explore potential mechanisms and management strategies for PI3K inhibitor toxicities.
Main Methods:
- Literature review focusing on PI3K inhibitors in cancer therapy.
- Analysis of clinical development and adverse event profiles.
- Discussion of proposed mechanisms and management approaches for toxicities.
Main Results:
- PI3K inhibitors are effective anticancer agents but associated with significant toxicities.
- Adverse effects are often on-target and immune-mediated, with unclear underlying mechanisms.
- Isoform-specific inhibitors are a key area of development.
Conclusions:
- Comprehensive understanding of PI3K inhibitor adverse events is needed.
- Effective management guidelines, optimized dosing, and combination therapies are essential for safe clinical application.
- Further research into mechanisms and management of toxicities is required to maximize therapeutic benefit.
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