Akt as a target for cancer therapy: more is not always better (lessons from studies in mice)

Area of Science:

• Molecular Biology
• Cancer Research
• Pharmacology

Background:

• The PI3K/Akt pathway is frequently dysregulated in human cancers, making it a key therapeutic target.
• Current anticancer therapies targeting this pathway show promise but are associated with adverse effects like hyperglycemia.
• Understanding the in vivo consequences of Akt inhibition is crucial for safe and effective cancer treatment.

Purpose of the Study:

• To review and discuss the consequences of genetic Akt isoform deletions in adult mice.
• To evaluate the implications of these findings for developing targeted cancer therapies.
• To understand the organismal-level effects of Akt isoform inhibition.

Main Methods:

• Review of studies involving genetic deletions of Akt isoforms in adult mice.
• Analysis of the phenotypic outcomes and survival data following isoform-specific gene knockouts.
• Correlation of findings with observed side effects of pan-PI3K and pan-Akt inhibitors.

Main Results:

• Combined deletion of Akt1 and Akt2 in mice led to rapid mortality.
• Inhibition of Akt in the liver induced liver injury, promoting hepatocellular carcinoma.
• These results highlight isoform-specific functions and potential toxicity of broad Akt inhibition.

Conclusions:

• Systemic inhibition of all Akt isoforms may lead to severe adverse events and mortality.
• Targeting specific Akt isoforms might be a more viable strategy for cancer therapy.
• Further research is needed to carefully consider the risks associated with targeting the PI3K/Akt pathway.