RESUMEN

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. FINDINGS: 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.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Genes ras , Neoplasias Pulmonares/radioterapia , Malato Deshidrogenasa/biosíntesis , Proteínas de Neoplasias/biosíntesis , Animales , Aspartato Aminotransferasa Citoplasmática/biosíntesis , Aspartato Aminotransferasa Citoplasmática/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Bases de Datos Factuales , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/genética , Glutamina/metabolismo , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Malato Deshidrogenasa/análisis , Malato Deshidrogenasa/genética , Ratones , Ratones Transgénicos , Mutación Missense , NADP/metabolismo , Proteínas de Neoplasias/análisis , Proteínas de Neoplasias/genética , Oxidación-Reducción , Mutación Puntual , Pronóstico , Interferencia de ARN , ARN Mensajero/biosíntesis , ARN Neoplásico/biosíntesis , ARN Interferente Pequeño/genética , Tolerancia a Radiación/genética , Proteínas Recombinantes de Fusión/biosíntesis , Ensayo de Tumor de Célula Madre , Regulación hacia Arriba