Normoxic or hypoxic adaptation in response to antiangiogenic therapy: Clinical implications

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Acquired resistance to antiangiogenic tyrosine-kinase inhibitors (TKIs) is a significant clinical challenge.
• Vascular normalization-inducing TKIs target tumor angiogenesis by blocking glycolysis.

Purpose of the Study:

• To elucidate the novel mechanism of acquired resistance to vascular normalization-inducing TKIs.
• To identify targetable metabolic pathways involved in TKI resistance.

Main Methods:

• Analysis of tumor metabolic reprogramming in response to TKI treatment.
• Investigation of the role of glycolysis and mitochondrial metabolism in acquired resistance.

Main Results:

• TKIs induce a nutritional stress response by blocking tumor glycolysis.
• This stress triggers a switch to mitochondrial metabolism, conferring acquired resistance.
• This metabolic switch represents a targetable vulnerability.

Conclusions:

• Acquired resistance to TKIs involves a metabolic shift to mitochondrial respiration.
• Targeting this metabolic adaptation may overcome TKI resistance.
• Further clinical and translational research is warranted.