Enhanced glucose uptake and increased glycolysis are hallmarks of tumor cells. Building on key preliminary results generated in the past years, the Laboratory of Cancer Metabolism is studying a strategy for exploiting these peculiar metabolic characteristics for cancer therapy.
KRAS-mutant colorectal tumors display an exceptionally high glycolysis rate, which makes them ‘addicted’ to glucose. This dependency suggests a potential therapeutic approach based on anti-glycolytic agents, including drugs used for treating diabetes. However, preliminary experiments conducted in our lab suggest that Hepatocyte Growth Factor (HGF), a cytokine that is abundant in the tumor micro-environment, can rescue KRASmutant CRC cells from starvation-induced apoptosis. Based on this evidence, we hypothesized that inhibition of HGF or its receptor MET would render KRAS-mutant tumors more sensitive to anti-metabolic therapy.
We selected a panel of metabolism-targeting drugs that affected glucose metabolism by different mechanisms and at different levels, including metformin and phenformin (both inhibitors of mitochondrial complex I), dichloroacetate (an inhibitor of pyruvate dehydrogenase kinase), and WZB-117 (an inhibitor of the facilitative glucose transporter GLUT1). Pharmacological analysis of these drugs in isogenic KRAS CRC cell lines revealed that CRC cell clones expressing mutant KRAS are dramatically more sensitive than their wild-type KRAS counterpart to glucose deprivation or to treatment with metformin, phenformin, dichloroacetate or WZB-117. Apoptosis analysis showed that all of these anti-metabolic agents were causing a pronounced increase in the percentage of apoptotic cells, which could be prevented or mitigated by recombinant HGF. In an orthotopic mouse model of KRAS-mutant CRC using human HGF knock-in SCID mice, metformin inhibited tumor growth and inhibited hepatic and pulmonary metastasis. Moreover, anti-metabolic drugs cooperated with the HGF-neutralizing antibody ficlatuzumab in inhibiting tumor growth and in suppressing metastasis.
Conclusions and perspectives
These preliminary data strongly suggest that KRAS-mutant CRC cell metabolic vulnerability can be exploited therapeutically by interfering with glucose metabolism. They also point at micro-environment-derived HGF as a major source of resistance to any kind of therapy that causes metabolic stress to KRAS-mutant CRC cells. Research in the Laboratory of Cancer Metabolism focuses on how to transfer this knowledge into clinical practice.