Hypermetabolic cancer cells resist to chemotherapy

2017 - 06 - 08

Hypermetabolic cancer cells resist to chemotherapy

A study led by the team RESISTAML of the Cancer Research Centre of Toulouse (Inserm, France), involving Toulouse University Hospital and LIH, revealed new findings about the molecular mechanisms of drug resistance in human acute myeloid leukaemia. It demonstrated that not resting leukemic stem cells - as initially thought - are responsible for resistance to treatment and relapse, but cancer cells with a highly active energy metabolism.

Acute myeloid leukaemia (AML) is a cancer type characterised by a clonal disorder of the myeloid line of blood cells. It leads to the rapid growth of abnormally differentiated myeloid cells that build up in the bone marrow and interfere with the production of normal blood cells. Several months after an apparently successful chemotherapy, AML patients often relapse. It was hypothesised that this is due to chemo-resistant immature leukemic stem cells that survive. The present research work revisits this assumption and indicates that cells with high metabolic activity are those resistant to chemotherapy.

In this study, published in April 2017 in Cancer Discovery, one of the top ten journals in oncology (impact factor 19.78), the scientists used mouse models mimicking disease evolution from patients' cells. When treating the animals with the chemotherapeutic agent cytarabine, they observed that the treatment killed both resting and proliferating cancer cells and that the remaining chemo-resistant cells presented a high energetic status, meaning an increased function of their mitochondria.

The resistance of leukemic cells thus seems to depend on their metabolic activity, which could be a potential target for new therapeutic approaches. The scientists tested pharmacological agents inhibiting mitochondrial metabolism in combination with chemotherapy and could show that treatment efficacy was enhanced. ‘The outcomes of this publication could lead to new therapeutic strategies already tested in early clinical trials, not only for AML but also for other cancer types in which mitochondrial hyperactivity has been described’ emphasises principal investigator Dr Jean-Emmanuel Sarry.

Tony Kaoma and Dr Laurent Vallar, scientists with the Proteome and Genome Research Unit at LIH’s Department of Oncology, contributed to this important study with their expertise in bioinformatics and genomics, respectively. ‘Our know-how was already valued in previous collaborations with the team from Toulouse’, says bioinformatician Tony Kaoma. ‘For the present study, we conducted microarray experiments with the biological samples and performed full genome transcriptomic analysis of all data sets. We proposed a gene signature able to predict patient response to chemotherapy’. A follow-up study involving LIH is planed that will include more patients and other omics data in order to improve the prediction model.

Publication: Chemotherapy Resistant Human Acute Myeloid Leukemia Cells are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism