RESUMO
The high-mobility group box 1 (HMGB1) protein has a central role in immunological antitumour defense. Here we show that natural killer cell-derived HMGB1 directly eliminates cancer cells by triggering metabolic cell death. HMGB1 allosterically inhibits the tetrameric pyruvate kinase isoform M2, thus blocking glucose-driven aerobic respiration. This results in a rapid metabolic shift forcing cells to rely solely on glycolysis for the maintenance of energy production. Cancer cells can acquire resistance to HMGB1 by increasing glycolysis using the dimeric form of PKM2, and employing glutaminolysis. Consistently, we observe an increase in the expression of a key enzyme of glutaminolysis, malic enzyme 1, in advanced colon cancer. Moreover, pharmaceutical inhibition of glutaminolysis sensitizes tumour cells to HMGB1 providing a basis for a therapeutic strategy for treating cancer.
Assuntos
Neoplasias do Colo/metabolismo , Neoplasias do Colo/fisiopatologia , Proteína HMGB1/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Morte Celular , Linhagem Celular Tumoral , Respiração Celular , Neoplasias do Colo/enzimologia , Neoplasias do Colo/genética , Glucose/metabolismo , Glicólise , Proteína HMGB1/genética , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Hormônios Tireóideos/genética , Hormônios Tireóideos/metabolismo , Proteínas de Ligação a Hormônio da TireoideRESUMO
UNLABELLED: The German AMNOG healthcare reform includes a mandatory early-benefit-assessment (EBA) at launch. As per German social code, EBA is based on registration trials and includes evaluation of the patient-relevant effect of the new medicines compared to an appropriate comparator as defined by the Federal Joint Committee (G-BA). Current EBA decisions released have unveiled issues regarding the acceptance of some patient-relevant endpoints as G-BA and IQWiG are grading the endpoints, focusing on overall survival as the preferred endpoint in oncology.A taskforce of experienced German outcomes research, medical, health-technology assessment and biostatistics researchers in industry was appointed. After agreement on core assumptions, a draft position was prepared. Input on iterative versions was solicited from a panel of reviewers from industry and external stakeholders.Distinctive features of registration trials in oncology need to be considered when these studies form basis for EBA, especially in cancer-indications with long post-progression survival; and with several consecutive therapeutic options available post-progression. Ethical committees, caregivers and patients often demand cross-over-designs diluting the treatment-effect on overall survival. Regulatory authorities require evaluation of morbidity-related study endpoints including survival of patients without their disease getting worse (i.e., progression-free survival). Also, progression requires treatment-changes, another strong indicator for its relevance to patients.Based on specific guidelines and clinical trial programs that were developed to be consistent with regulatory guidance, endpoints in oncology are thoroughly evaluated in terms of their patient-relevance. This extensive knowledge and experience should be fully acknowledged during EBA when assessing the patient-relevant benefit of innovative medicines in oncology. JEL CODES: D61; H51; I18.