Project Grant R37CA285640

UNCOVERING ONCOGENOTYPE-SPECIFIC VULNERABILITIES IN LUNG CANCER - PROJECT SUMMARY GIVEN THE IMPORTANT ROLES OF TUMOR SUPPRESSORS AND ONCOGENES IN METABOLIC REPROGRAMMING, THERE IS SIGNIFICANT TRANSLATIONAL POTENTIAL IN IDENTIFYING AND UNDERSTANDING HOW PARTICULAR ONCOGENOTYPES INFLUENCE TUMOR METABOLISM, AND WHETHER THESE CHANGES IMPOSE LIABILITIES THAT CAN BE EXPLOITED THERAPEUTICALLY. FROM MORE RECENT STUDIES, HOWEVER, A NUANCED PICTURE HAS EMERGED SHOWING THAT TISSUE CONTEXT IMPACTS THE EXECUTION OF METABOLIC REPROGRAMMING EVEN WITH THE SAME ONCOGENIC DRIVERS. FOR EXAMPLE, DESPITE HAVING THE SAME DRIVER MUTATIONS, PANCREATIC CANCER AND LUNG CANCER EXHIBIT DIFFERENCES IN BRANCHED CHAIN AMINO ACID (BCAA) METABOLISM, WHERE LUNG TUMORS INCREASE BCAA UPTAKE TO USE THEM AS A NITROGEN SOURCE WHILE PANCREATIC TUMORS DECREASE BCAA UPTAKE DUE TO DECREASED EXPRESSION OF GENES IN BCAA METABOLISM COMPARED WITH NORMAL PANCREAS. THUS, UNDERSTANDING HOW CELL-OF-ORIGIN INTERACTS WITH GENETIC EVENTS TO AFFECT THE METABOLIC DEPENDENCE OF TUMORS WILL BE CRITICAL FOR SELECTING THE RIGHT TREATMENT APPROACHES FOR PATIENTS. BY ANALYZING THE METABOLOME OF HUMAN NON-SMALL CELL LUNG CANCER (NSCLC) SAMPLES SURGICALLY RESECTED FROM PATIENTS AND COMPARING THOSE WITH KRAS MUTATIONS (K) TO THOSE WITH KRAS/LKB1 CO-MUTATIONS (KL), WE NOTED THAT SERINE-GLYCINE ONE CARBON (SGOC) METABOLISM IS SIGNIFICANTLY ALTERED IN KL NSCLC, SIMILAR TO KL PANCREATIC CANCER MODELS. BY FURTHER METABOLIC ANALYSES, HOWEVER, WE CLARIFIED THE DIFFERENCES IN SGOC METABOLISM BETWEEN THESE TWO TUMOR TYPES. WHILE KL PANCREATIC CANCER REQUIRES SGOC FOR DNA METHYLATION, KL NSCLC DEPENDS ON SGOC VIA SERINE HYDROXYMETHYLTRANSFERASE (SHMT) ENZYMES TO MAINTAIN REDOX HOMEOSTASIS. BY ESTABLISHING BOTH MOLECULAR AND METABOLIC PLATFORMS TO MEASURE METABOLITES INVOLVED IN REDOX BALANCE, AND UTILIZING CLINICALLY RELEVANT MOUSE MODELS FOR IN VIVO STUDIES, WE ARE NOW POISED TO DEFINE THE ONCOGENIC ROLE OF SHMTS DURING LUNG TUMORIGENESIS. IN AIM 1 WE WILL INTERROGATE THE MECHANISTIC BASIS OF SHMT DEPENDENCE IN THESE NSCLC CELLS. IN AIM 2 WE WILL INVESTIGATE THE MOLECULAR MECHANISM BY WHICH LKB1 REGULATES SHMT. IN AIM 3 WE WILL EXAMINE 1) WHETHER SHMT SUPPRESSION REDUCES TUMOR GROWTH AND 2) WHETHER THE COMBINATION OF SHMT INHIBITION WITH CHEMOTHERAPEUTIC DRUGS THAT INDUCE OXIDATIVE STRESS CAN FURTHER INHIBIT TUMOR GROWTH USING VARIOUS MOUSE MODELS. WHILE THE CRITICAL ROLE OF SGOC AS A METHYL GROUP DONOR FOR DNA METHYLATION IN KL PANCREATIC CANCER HAS BEEN REPORTED, THE IMPORTANCE OF SGOC METABOLISM IN KL NSCLC OR HETEROGENEITY BETWEEN THESE TWO DISEASES HAS YET TO BE ELUCIDATED. OUR STUDIES WILL PROVIDE VALUABLE INFORMATION FOR SUBSTRATIFICATION OF NSCLC PATIENTS WITH HYPERACTIVE SGOC METABOLISM AS TREATMENT RESPONDERS TO THERAPIES TARGETING REDOX BALANCE, WHICH IS PERTINENT TO THE GOALS OF PRECISION MEDICINE.