title: Mutant KRAS associated malic enzyme 1 expression is a predictive marker for radiation therapy response in non-small cell lung cancer.
abstract: BACKGROUND
  Advanced non-small cell lung cancer (NSCLC) is an aggressive tumor that is treated with a combination of chemotherapy and radiation if the patient is not a candidate for surgery. Predictive biomarkers for response to radiotherapy are lacking in this patient population, making it a non-tailored therapy regimen with unknown outcome. Twenty to 30 % of NSCLC harbor an activating mutation in KRAS that may confer radioresistance. We hypothesized that mutant KRAS can regulate glutamine metabolism genes in NSCLC and maintain tumor redox balance through transamination reactions that generate cytosolic NADPH via malic enzyme 1 (ME1), which may contribute to radioresistance.
  
  
  RESULTS
  A doxycycline-inducible mouse model of KRAS (G12D) driven NSCLC and patient data was analyzed from multiple publicly accessible databases including TCGA, CCLE, NCBI GEO and Project Achilles. ME1 expression was found to be mutant KRAS associated in both a NSCLC mouse model and human NSCLC cancer cell lines. Perturbing glutamine metabolism sensitized mutant KRAS, but not wild-type KRAS NSCLC cell lines to radiation treatment. NSCLC survival analysis revealed that patients with elevated ME1 and GOT1 expression had significantly worse outcomes after radiotherapy, but this was not seen after chemotherapy alone.
  
  
  CONCLUSIONS
  KRAS driven glutamine metabolism genes, specifically ME1 and GOT1 reactions, may be a predictive marker and potential therapeutic target for radiotherapy in NSCLC.
authors.affiliation: Departments of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA. gaurab.chakrabarti@utsouthwestern.edu.|Departments of Radiation Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA. gaurab.chakrabarti@utsouthwestern.edu.|Departments of Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA. gaurab.chakrabarti@utsouthwestern.edu.|University of Texas Southwestern Medical Center, 6001 Forest Park Drive, ND 2.210, Dallas, TX, 75390-8807, USA. gaurab.chakrabarti@utsouthwestern.edu.
authors.forename: Gaurab
authors.initials: G
authors.lastname: Chakrabarti
mesh_terms: D000818:Animals; D024443:Aspartate Aminotransferase, Cytoplasmic / Q000096:biosynthesis / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D016208:Databases, Factual; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D011905:Genes, ras; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D008291:Malate Dehydrogenase / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009249:NADP / Q000378:metabolism; D009363:Neoplasm Proteins / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D010084:Oxidation-Reduction; D017354:Point Mutation; D011379:Prognosis; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014410:Tumor Stem Cell Assay; D015854:Up-Regulation
chemical_list: D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D005973:Glutamine; D009249:NADP; D008291:Malate Dehydrogenase; C030574:malate dehydrogenase (decarboxylating); D024443:Aspartate Aminotransferase, Cytoplasmic