RESUMEN
In non-small-cell lung cancer (NSCLC), concurrent mutations in the oncogene KRAS and the tumour suppressor STK11 (also known as LKB1) encoding the kinase LKB1 result in aggressive tumours prone to metastasis but with liabilities arising from reprogrammed metabolism. We previously demonstrated perturbed nitrogen metabolism and addiction to an unconventional pathway of pyrimidine synthesis in KRAS/LKB1 co-mutant cancer cells. To gain broader insight into metabolic reprogramming in NSCLC, we analysed tumour metabolomes in a series of genetically engineered mouse models with oncogenic KRAS combined with mutations in LKB1 or p53. Metabolomics and gene expression profiling pointed towards activation of the hexosamine biosynthesis pathway (HBP), another nitrogen-related metabolic pathway, in both mouse and human KRAS/LKB1 co-mutant tumours. KRAS/LKB1 co-mutant cells contain high levels of HBP metabolites, higher flux through the HBP pathway and elevated dependence on the HBP enzyme glutamine-fructose-6-phosphate transaminase [isomerizing] 2 (GFPT2). GFPT2 inhibition selectively reduced KRAS/LKB1 co-mutant tumour cell growth in culture, xenografts and genetically modified mice. Our results define a new metabolic vulnerability in KRAS/LKB1 co-mutant tumours and provide a rationale for targeting GFPT2 in this aggressive NSCLC subtype.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Hexosaminas/biosíntesis , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Redes y Vías Metabólicas , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Azaserina/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Línea Celular Tumoral , Inhibidores Enzimáticos/farmacología , Regulación Neoplásica de la Expresión Génica , Glutamina-Fructosa-6-Fosfato Transaminasa (Isomerizadora)/antagonistas & inhibidores , Glutamina-Fructosa-6-Fosfato Transaminasa (Isomerizadora)/genética , Humanos , Neoplasias Pulmonares/mortalidad , Metabolómica , Ratones , Mutación , Análisis de Supervivencia , Ensayo de Tumor de Célula MadreRESUMEN
There is evidence to suggest that the extra nuclear cell constituents are the part of the cell which contains all the biochemical mechanisms responsible for implementing all cell functions. These functions include control of cell division, growth, response to injury, replacement of effete cells, maintenance of anatomical and spatial cellular relations and specific cellular function and structure. The energy to perform these functions is derived from the aerobic metabolism of glucose. The energy required for nuclear division appears to be wholly or partly derived from the anaerobic metabolism of glucose. Ethyl alcohol interferes with the aerobic metabolic pathways and thus disrupts or diminishes all aerobically activated cell functions. The speed of all activities motivated by aerobic glycolysis can be increased by appropriate electrical stimulations delivered from any of a range of electromagnetic radiation frequencies tested. In addition to the stimulant effect on aerobic metabolic processes, 434 MHz can stimulate the anaerobic glucose metabolism of cancer with consequent stimulation of cancer growth rate. 434 MHz appears to deliver energy to the anaerobic cancer metabolism by causing a resonance phenomenon amongst one or more of the substrates which comprise the first few stages of glycolysis. This phenomenon permits the selective delivery of electromagnetic radiation energy to cancer cells which, if sufficiently intense, causes injury to cancer cells without harm to the normal cells except when the latter are in the phase of anaerobic metabolism which occurs at some stage of the mitotic cycle. Streptokinase, ethanol and glucose analogues increase the lethal effects on cancers undergoing therapy with 434 MHz radiation and observations of such responses suggest a theoretical basis to explain the rare spontaneous remissions of human cancer. Cancer appears to protect its glucose supplies by elevating the blood glucose levels above normal and by some mechanism which reduces the effectiveness of the body's control of its fasting glucose level. The serum fibrinogen level rises when cancer involves the abdominal viscerae, particularly the liver. A raised serum fibrinogen level appears to be a direct indication that the liver must be included in the treatment regime if longer survival is desired. If the level cannot be corrected then death of that individual appears assured.
Asunto(s)
Citoplasma/fisiología , Fenómenos Electromagnéticos , Mitosis , Neoplasias/terapia , Adulto , Anciano , Azaserina/uso terapéutico , División Celular , Etanol/uso terapéutico , Femenino , Fibrinógeno/metabolismo , Hexosas/uso terapéutico , Calor , Humanos , Insulina/uso terapéutico , Masculino , Persona de Mediana Edad , Neoplasias/metabolismo , Estreptoquinasa/uso terapéutico , Cicatrización de HeridasRESUMEN
A review of the clinical data on azaserine, DON, and azotomycin reveals that these agents have limited but definite antitumor activity. All three drugs are analogs of L-glutamine and contain a diazo group. They have been studied as single agents in a wide variety of human malignancies and have also been included in trials using combination chemotherapy. Most of these studies were performed early in the history of clinical trials and, therefore, the method of reporting results and the evaluation criteria were quite different from those in use today. A renewed interest in these agents has been triggered by the remarkable activity of DON and azotomycin against human tumor lines implanted into nude mice. On the basis of this activity and the clinical data we have compiled, we feel that new clinical trials with these agents are warranted.
Asunto(s)
Azaserina/uso terapéutico , Compuestos Azo/uso terapéutico , Diazooxonorleucina/uso terapéutico , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/administración & dosificación , Neoplasias del Colon/tratamiento farmacológico , Evaluación de Medicamentos , Quimioterapia Combinada , Femenino , Humanos , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Neoplasias Experimentales/tratamiento farmacológico , Trasplante HeterólogoRESUMEN
A model of the phenomenon of selectivity of antineoplastic phase-specific preparations in leukemia, based on the assumption that any proliferating cells are equally sensitive to the action of such preparations, is suggested. Therefore, selectivity, the concept and fundamental significance of which were formulated and substantiated by the authors earlier, can be expressed in terms of the proliferative pathways of the normal and leukemic populations, the ratio between which thus plays the deciding role in the selection of the optimum system of therapy. The concept of maximum selectivity, which is a convenient numerical characteristic of a preparation, was introduced. A comparative quantitative analysis was made of a number of antineoplastic preparations (vinblastine, vincristine, amethopterin, arabinosylcytosine, azaserine); it showed that the conclusions of the model do not contradict the experimental data.