Metabolic Vulnerabilities in Lung Squamous Cell Carcinoma
Elucidating and Targeting the Glycolytic Dependence of Lung Squamous Cell Carcinoma
Lung cancer is a leading cause of cancer related death in both developed and developing countries and has a higher mortality rate than colorectal, breast, and prostate cancers combined. Lung squamous cell carcinoma (SqCC), a subtype of lung cancer, accounts for 25-30% of all lung cancers. Although much research into lung cancer and possible treatments are being investigated, not much focus has been given to lung squamous cell carcinoma. For instance, lung SqCC, which accounts for 25-30% of all human lung cancers, has benefited very little from the application of targeted therapeutic options, as a result, decades old platinum-based chemotherapy regiments remain the first-line treatment options. Therefore, identification of targetable vulnerabilities in lung SqCC is imperative to improve therapeutic outcome of SqCC patients.
Lung SqCC xenograft stained with GLUT1 (green) and p63 (pink) shows significantly elevated GLUT1 expression correlating with SqCC marker p63.
PET scan of ADC/SqCC xenografts show high glucose consumption in only the SqCC tumor.
There is an increasing body of evidence arguing for substantial heterogeneity in how individual cancers utilize glucose in promoting tumorigenesis. We recently reported that lung SqCC exhibits distinctively elevated GLUT1 expression resulting in high susceptibility to glycolytic inhibition whereas lung adenocarcinoma (ADC) is significantly less reliant on glucose and thereby resistant to glycolytic inhibition. Our group is focused on elucidating the molecular mechanisms underlying this previously unrecognized GLUT1-mediated glucose metabolism in lung squamous cancers. Targeting cancer glycolysis, on the assumption that glycolytic metabolism is uniformly elevated in most human cancers, has proven to be clinically unsatisfactory. Our discovery of distinct and exceptional glycolytic signature and glucose reliance phenotypically linked to lung SqCC argue that lung SqCC can be uniquely vulnerable to glucose restriction.