Identification of metabolic vulnerabilities of receptor tyrosine kinases-driven cancer

Area of Science:

• Oncology
• Cancer Metabolism
• Molecular Biology

Background:

• Identifying patient subsets responsive to metabolism-targeted therapies remains a significant challenge in cancer treatment development.
• Metabolic vulnerabilities in most human cancers are not well understood, hindering the design of effective therapies.
• Receptor tyrosine kinases (RTK) represent well-defined cancer genotypes, offering a potential link to metabolic dependencies.

Purpose of the Study:

• To establish a link between distinct metabolic signatures and oncogenic alterations in receptor tyrosine kinases (RTK).
• To guide metabolic interventions towards specific patient populations based on their cancer genotype.
• To uncover the molecular basis for patient stratification in metabolism-targeted cancer therapies.

Main Methods:

• Integrated analysis of metabolomics and transcriptomics data from cancer samples.
• Investigated the metabolic consequences of specific RTK activations, including EGFR and FGFR.
• Correlated genetic alterations with responsiveness to targeted pharmacological inhibitors.

Main Results:

• Oncogenic RTK activation leads to distinct metabolic preferences.
• EGFR activation directs glycolysis towards serine synthesis for nucleotide biosynthesis and redox balance.
• FGFR activation promotes lactate recycling to fuel oxidative phosphorylation for energy production.

Conclusions:

• EGFR and FGFR alterations stratify tumors responsive to inhibitors targeting serine synthesis and lactate metabolism, respectively.
• This study provides a molecular link between cancer genotypes and metabolic dependencies.
• The findings offer a basis for patient stratification in the development of metabolism-targeted therapies.