Tumor vascular changes mediated by inhibition of oncogenic signaling

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• The epidermal growth factor receptor (EGFR)-RAS-phosphatidylinositol 3-kinase (PI3K)-AKT pathway is a key target in cancer therapy.
• Inhibitors targeting this pathway are widely used or under development for various cancers.

Purpose of the Study:

• To investigate the effects of inhibiting the EGFR-RAS-PI3K-AKT pathway on tumor vasculature.
• To determine if these vascular changes are therapeutically relevant and durable.

Main Methods:

• Treatment of mice with human tumor xenografts and spontaneously arising tumors with inhibitors of EGFR, RAS, PI3K, or AKT.
• Assessment of tumor vascular flow, perfusion, hypoxia, and vessel morphology.
• Evaluation of tumor growth inhibition and EGFR expression in tumor cells.

Main Results:

• Inhibition of RAS, PI3K, or AKT signaling led to prolonged enhancement of tumor vascular flow, perfusion, and decreased hypoxia.
• Tumor vessels showed reduced tortuosity and increased internodal length.
• Vascular changes occurred independently of direct tumor growth inhibition and were observed in EGFR-expressing tumors but not in EGFR-deficient tumors treated with an EGFR inhibitor.
• Similar vascular normalization, including increased maturity and pericyte marker acquisition, was observed in spontaneously arising tumors treated with PI3K inhibition.

Conclusions:

• Blocking tumor cell RAS-PI3K-AKT signaling induces persistent vascular normalization, characterized by improved blood flow and reduced hypoxia.
• These findings suggest that targeting this signaling pathway can be a viable strategy for improving cancer therapy through vascular normalization.
• Vascular alterations should be considered a significant consequence of signaling pathway inhibition in cancer treatment.