Targeting Metabolic Survival Pathways in Lung Cancer via Combination Therapy
Annual rept. 1 June 2013 to 31 May 2014
CALIFORNIA UNIV SAN DIEGO LA JOLLA
Pagination or Media Count:
This proposal aims to identify critical metabolic pathways necessary for survival of liver kinase B1 LKB1-deficient non-small cell lung cancer NSCLC cell lines. We have conducted 13C metabolic flux analysis studies in LKB1 proficient or deficient NSCLC cells under nutrient complete or metabolic stress conditions e.g. hypoxia, matrix detachment. Using these analyses we can demonstrate that cells lacking the LKB1 tumor suppressor exhibit limited oxidation of glucose-derived pyruvate in mitochondria. LKB1-deficient cells also exhibit increased reliance on glutamine metabolism. Treatment with biguanides such as metformin or phenformin decreases oxidative mitochondrial metabolism. A critical defect we have observed in our analyses is the inability of LKB1- deficient tumor cells to recover in response to phenformin treatment, as carbohydrate oxidation remains compromised for an extended period of time after removalwashout of phenformin. Given the dependence of LKB1-deficient tumor cells on glutamine metabolism, we are targeting a critical enzyme responsible for catalyzing the entry of glutamine carbon into the Krebs cycle in mitochondria, glutaminase.
- Medicine and Medical Research