Metabolic adaptation towards glycolysis supports resistance to neoadjuvant chemotherapy in early triple negative breast cancers.

Autor: Derouane F; Pole of Medical Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, 1200, Brussels, Belgium.; Department of Medical Oncology, King Albert II Cancer Institute, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200, Brussels, Belgium.; Breast Clinic, King Albert II Cancer Institute, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200, Brussels, Belgium., Desgres M; Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, 1200, Brussels, Belgium., Moroni C; Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, 1200, Brussels, Belgium., Ambroise J; Centre des Technologies Moléculaires Appliquées (CTMA), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 54, 1200, Brussels, Belgium., Berlière M; Breast Clinic, King Albert II Cancer Institute, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200, Brussels, Belgium.; Department of Gynecology, King Albert II Cancer Institute, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200, Brussels, Belgium.; Pole of Gynecology (GYNE), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Mounier 52, 1200, Brussels, Belgium., Van Bockstal MR; Breast Clinic, King Albert II Cancer Institute, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200, Brussels, Belgium.; Department of Pathology, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200, Brussels, Belgium., Galant C; Breast Clinic, King Albert II Cancer Institute, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200, Brussels, Belgium.; Department of Pathology, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200, Brussels, Belgium.; Pole of Morphology (MORF), Institut de Recherche Expérimentale Et Clinique (IREC), UCLouvain, Avenue Mounier 52, 1200, Brussels, Belgium., van Marcke C; Pole of Medical Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, 1200, Brussels, Belgium.; Department of Medical Oncology, King Albert II Cancer Institute, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200, Brussels, Belgium.; Breast Clinic, King Albert II Cancer Institute, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200, Brussels, Belgium., Vara-Messler M; Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, 1200, Brussels, Belgium.; Sanofi Belgium, 9052, Zwijnaarde, Belgium., Hutten SJ; Division of Molecular Pathology, The Netherlands Cancer Institute, 1066CX, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Jonkers J; Division of Molecular Pathology, The Netherlands Cancer Institute, 1066CX, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Mourao L; Laboratory for Intravital Imaging and Dynamics of Tumor Progression, VIB Center for Cancer Biology, KU Leuven, 3000, Leuven, Belgium.; Department of Oncology, KU Leuven, 3000, Louvain, Belgium., Scheele CLGJ; Laboratory for Intravital Imaging and Dynamics of Tumor Progression, VIB Center for Cancer Biology, KU Leuven, 3000, Leuven, Belgium.; Department of Oncology, KU Leuven, 3000, Louvain, Belgium., Duhoux FP; Pole of Medical Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, 1200, Brussels, Belgium.; Department of Medical Oncology, King Albert II Cancer Institute, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200, Brussels, Belgium.; Breast Clinic, King Albert II Cancer Institute, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200, Brussels, Belgium., Corbet C; Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, 1200, Brussels, Belgium. cyril.corbet@uclouvain.be.
Jazyk: angličtina
Zdroj: Breast cancer research : BCR [Breast Cancer Res] 2024 Feb 19; Vol. 26 (1), pp. 29. Date of Electronic Publication: 2024 Feb 19.
DOI: 10.1186/s13058-024-01788-8
Abstrakt: Background: Neoadjuvant chemotherapy (NAC) is the standard of care for patients with early-stage triple negative breast cancers (TNBC). However, more than half of TNBC patients do not achieve a pathological complete response (pCR) after NAC, and residual cancer burden (RCB) is associated with dismal long-term prognosis. Understanding the mechanisms underlying differential treatment outcomes is therefore critical to limit RCB and improve NAC efficiency.
Methods: Human TNBC cell lines and patient-derived organoids were used in combination with real-time metabolic assays to evaluate the effect of NAC (paclitaxel and epirubicin) on tumor cell metabolism, in particular glycolysis. Diagnostic biopsies (pre-NAC) from patients with early TNBC were analyzed by bulk RNA-sequencing to evaluate the predictive value of a glycolysis-related gene signature.
Results: Paclitaxel induced a consistent metabolic switch to glycolysis, correlated with a reduced mitochondrial oxidative metabolism, in TNBC cells. In pre-NAC diagnostic biopsies from TNBC patients, glycolysis was found to be upregulated in non-responders. Furthermore, glycolysis inhibition greatly improved response to NAC in TNBC organoid models.
Conclusions: Our study pinpoints a metabolic adaptation to glycolysis as a mechanism driving resistance to NAC in TNBC. Our data pave the way for the use of glycolysis-related genes as predictive biomarkers for NAC response, as well as the development of inhibitors to overcome this glycolysis-driven resistance to NAC in human TNBC patients.
(© 2024. The Author(s).)
Databáze: MEDLINE
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