Metronomic Chemotherapy Modulates Clonal Interactions to Prevent Drug Resistance in Non-Small Cell Lung Cancer - Archive ouverte HAL Access content directly
Journal Articles Cancers Year : 2021

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

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Maryna Bondarenko
  • Function : Author
Marion Le Grand
Yuval Shaked
Ziv Raviv
  • Function : Author
Guillemette Chapuisat
Cécile Carrère
Marie-Pierre Montero
  • Function : Author
Mailys Rossi
  • Function : Author
Eddy Pasquier
  • Function : Author
Manon Carré
  • Function : Author

Abstract

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.

Dates and versions

hal-03625356 , version 1 (30-03-2022)

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Maryna Bondarenko, Marion Le Grand, Yuval Shaked, Ziv Raviv, Guillemette Chapuisat, et al.. Metronomic Chemotherapy Modulates Clonal Interactions to Prevent Drug Resistance in Non-Small Cell Lung Cancer. Cancers, 2021, 13 (9), pp.2239. ⟨10.3390/cancers13092239⟩. ⟨hal-03625356⟩

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