Therapeutic Potential of PI3K/AKT/mTOR Pathway in Gastrointestinal Stromal Tumors: Rationale and Progress

Area of Science:

• Oncology
• Molecular Biology
• Gastroenterology

Background:

• Gastrointestinal stromal tumors (GISTs) originate from interstitial cells of Cajal (ICCs).
• KIT and PDGFRA gene mutations drive most GISTs, leading to receptor tyrosine kinase (RTK) activation.
• Imatinib therapy improves GIST management, yet resistance necessitates alternative strategies.

Purpose of the Study:

• To review PI3K/AKT/mTOR pathway involvement in GIST development and resistance.
• To explore the link between mTOR downstream signals, including eukaryotic initiation factors (eIFs), and GIST pathogenesis.
• To identify potential novel therapeutic targets for GIST treatment.

Main Methods:

• Literature review of preclinical and clinical studies on PI3K/AKT/mTOR signaling in GISTs.
• Analysis of GIST mechanisms involving RTK autophosphorylation and downstream pathway activation.
• Investigation of mTOR downstream effectors, such as eIFs, in GIST development.

Main Results:

• The PI3K/AKT/mTOR pathway is crucial for GIST cell survival, proliferation, and resistance to therapy.
• Constitutive RTK activation frequently leads to PI3K/AKT/mTOR pathway dysregulation in GISTs.
• Targeting the PI3K/AKT/mTOR pathway is a promising therapeutic strategy currently under investigation.

Conclusions:

• The PI3K/AKT/mTOR pathway is a key player in GIST pathogenesis and imatinib resistance.
• Understanding mTOR downstream signaling, particularly involving eIFs, may reveal new therapeutic avenues for GIST.
• Targeted inhibition of the PI3K/AKT/mTOR pathway holds significant potential for improving GIST treatment outcomes.