AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity

Area of Science:

• Oncology
• Molecular Biology
• Cancer Signaling Pathways

Background:

• The PI3K-AKT pathway is frequently activated in tumors.
• Negative feedback, such as mTORC1-mediated inhibition, regulates this pathway.
• Understanding feedback mechanisms is crucial for effective cancer therapy.

Purpose of the Study:

• To investigate the effects of AKT inhibition on receptor tyrosine kinase (RTK) expression and signaling.
• To elucidate the mechanisms underlying AKT inhibition-induced RTK activation.
• To evaluate the therapeutic implications of targeting feedback loops in cancer treatment.

Main Methods:

• Analysis of RTK expression and phosphorylation in various tumor types following AKT inhibition.
• Investigation of the roles of mTORC1 and FOXO transcription factors in regulating RTK expression.
• Preclinical studies combining AKT and HER pathway inhibitors.

Main Results:

• AKT inhibition induces expression and phosphorylation of multiple RTKs, including HER3, IGF-1R, and insulin receptor, across diverse tumors.
• This induction is partly mediated by mTORC1 inhibition and partly by FOXO-dependent transcriptional activation.
• PI3K-AKT inhibitors can relieve feedback, activating RTK signaling and potentially reducing antitumor efficacy.
• Combined inhibition of AKT and HER kinase activity demonstrated enhanced efficacy in tumors where AKT suppresses HER3.

Conclusions:

• AKT inhibition triggers a feedback loop involving RTK upregulation, which can counteract therapeutic effects.
• Targeting this feedback mechanism, for example, by combining AKT and HER inhibitors, offers a promising strategy for enhancing cancer therapy efficacy.
• The findings highlight the importance of considering pathway crosstalk and feedback in the design of targeted cancer treatments.