Molecular basis for class side effects associated with PI3K/AKT/mTOR pathway inhibitors

Area of Science:

• Oncology
• Pharmacology
• Toxicology

Background:

• The phosphatidylinositide 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is a key target in cancer therapy.
• While numerous PI3K/AKT/mTOR inhibitors are in development and clinical use, severe adverse effects like hepatotoxicity and pneumonitis restrict their application.
• Understanding the mechanisms behind these toxicities is vital for improving drug development and clinical use.

Purpose of the Study:

• To profile the class effects of PI3K/AKT/mTOR inhibitors.
• To discuss potential molecular toxicological mechanisms underlying these adverse events.
• To inform future drug discovery and optimize the use of existing inhibitors.

Main Methods:

• Literature review of adverse effects associated with PI3K/AKT/mTOR inhibitors.
• Analysis of reported toxicological mechanisms.
• Synthesis of information for clinical, pharmaceutical, and toxicological researchers.

Main Results:

• PI3K/AKT/mTOR inhibitors exhibit class-specific adverse effects, including severe hepatotoxicity and pneumonitis.
• Potential molecular mechanisms contributing to these toxicities have been identified.
• Current understanding of these mechanisms remains incomplete.

Conclusions:

• Severe toxicities associated with PI3K/AKT/mTOR inhibitors impede drug approval and long-term clinical use.
• Further research is necessary to elucidate the mechanisms of PI3K/AKT/mTOR inhibitor-induced toxicities.
• Developing strategies to mitigate toxicity and accelerate new drug development is essential for advancing cancer therapy.