Metronomic Chemotherapy Modulates Clonal Interactions to Prevent Drug Resistance in Non-Small Cell Lung Cancer.

Autor: Bondarenko M; Centre de Recherche en Cancérologie de Marseille, Aix-Marseille Université, Inserm, CNRS, Institut Paoli Calmettes, 13273 Marseille, France.; Assistance Publique-Hopitaux de Marseille (AP-HM), Timone Hospital, 13385 Marseille, France., Le Grand M; Centre de Recherche en Cancérologie de Marseille, Aix-Marseille Université, Inserm, CNRS, Institut Paoli Calmettes, 13273 Marseille, France., Shaked Y; Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525433, Israel.; Metronomics Global Health Initiative, 13385 Marseille, France., Raviv Z; Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525433, Israel., Chapuisat G; Centrale Marseille, CNRS, Aix Marseille Université, 13013 Marseille, France., Carrère C; Institut Denis Poisson, Université d'Orléans, CNRS, 45100 Orléans, France., Montero MP; Centre de Recherche en Cancérologie de Marseille, Aix-Marseille Université, Inserm, CNRS, Institut Paoli Calmettes, 13273 Marseille, France., Rossi M; Centre de Recherche en Cancérologie de Marseille, Aix-Marseille Université, Inserm, CNRS, Institut Paoli Calmettes, 13273 Marseille, France., Pasquier E; Centre de Recherche en Cancérologie de Marseille, Aix-Marseille Université, Inserm, CNRS, Institut Paoli Calmettes, 13273 Marseille, France.; Metronomics Global Health Initiative, 13385 Marseille, France., Carré M; Centre de Recherche en Cancérologie de Marseille, Aix-Marseille Université, Inserm, CNRS, Institut Paoli Calmettes, 13273 Marseille, France., André N; Centre de Recherche en Cancérologie de Marseille, Aix-Marseille Université, Inserm, CNRS, Institut Paoli Calmettes, 13273 Marseille, France.; Assistance Publique-Hopitaux de Marseille (AP-HM), Timone Hospital, 13385 Marseille, France.; Metronomics Global Health Initiative, 13385 Marseille, France.; Service d'Hématologie & Oncologie Pédiatrique, AP-HM, 13385 Marseille, France.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2021 May 07; Vol. 13 (9). Date of Electronic Publication: 2021 May 07.
DOI: 10.3390/cancers13092239
Abstrakt: Despite recent advances in deciphering cancer drug resistance mechanisms, relapse is a widely observed phenomenon in advanced cancers, mainly due to intratumor clonal heterogeneity. How tumor clones progress and impact each other remains elusive. In this study, we developed 2D and 3D non-small cell lung cancer co-culture systems and defined a phenomenological mathematical model to better understand clone dynamics. Our results demonstrated that the drug-sensitive clones inhibit the proliferation of the drug-resistant ones under untreated conditions. Model predictions and their experimental in vitro and in vivo validations indicated that a metronomic schedule leads to a better regulation of tumor cell heterogeneity over time than a maximum-tolerated dose schedule, while achieving control of tumor progression. We finally showed that drug-sensitive and -resistant clones exhibited different metabolic statuses that could be involved in controlling the intratumor heterogeneity dynamics. Our data suggested that the glycolytic activity of drug-sensitive clones could play a major role in inhibiting the drug-resistant clone proliferation. Altogether, these computational and experimental approaches provide foundations for using metronomic therapy to control drug-sensitive and -resistant clone balance and highlight the potential of targeting cell metabolism to manage intratumor heterogeneity.
Databáze: MEDLINE
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