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Updated: Jan 16, 2026
Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
Transition between cell states of sensitivity reveals molecular vulnerability of drug-tolerant cells
Ludovic Peyre1, Marielle Péré1,2,3, Mickael Meyer1
1Université Côte d'Azur, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC, CNRS UMR 7275, Inserm 1323), 06560, Valbonne, Sophia Antipolis, France.
Abstract:
Drug-tolerant cells to pro-apoptotic treatments exhibit transient resistance to subsequent challenges, which can be sustained via transcriptional and translational regulations. Although persister cells have been described in other cell death modalities, how they respond to subsequent treatments that are different from the one they originate from remains less explored. Here we show that drug-tolerant cells to pro-apoptotic treatments exhibit a reduced capacity to activate caspase-8, as well as higher levels of RIPK3 protein expression. As this apoptosis-tolerant cell state exhibits features of vulnerability to necroptosis, we show that alternating from apoptotic to necroptotic treatments increases cell response compared to drug holiday or sustained treatment. To gain insights on these transitions between states of vulnerability to cell death, we developed a compartmental model explaining the emergence of drug-tolerant cell populations, and the fluxes between drug-sensitivity states. We found that drug-sensitivity states coexist in a clonal population of cancer cells with continuous transitions between them, which are sufficient to explain both the sustained resistance to repeated treatments and how alternating drug treatments ameliorates the overall treatment efficacy.
Insights
Drug-tolerant cancer cells resist apoptosis but are vulnerable to necroptosis. Alternating treatments, shifting between apoptosis and necroptosis, significantly improves cancer cell death compared to continuous or no treatment.
Area of Science:
- Cellular biology
- Cancer research
- Drug resistance
Background:
- Drug-tolerant cells can exhibit transient resistance to treatments.
- Understanding how these cells respond to different cell death modalities is crucial.
Purpose of the Study:
- To investigate the response of drug-tolerant cells to sequential, alternating treatments.
- To explore the mechanisms underlying transitions between drug-sensitivity states.
Main Methods:
- Characterization of drug-tolerant cells' response to pro-apoptotic and necroptotic treatments.
- Development of a compartmental model to study cell population dynamics and drug sensitivity transitions.
Main Results:
- Apoptosis-tolerant cells show reduced caspase-8 activation and increased RIPK3 expression, indicating vulnerability to necroptosis.
- Alternating apoptotic and necroptotic treatments enhanced cell death compared to sustained treatment or drug holidays.
- A compartmental model demonstrated that coexisting drug-sensitivity states and their transitions explain sustained resistance and improved alternating treatment efficacy.
Conclusions:
- Drug-tolerant cell states are dynamic, with continuous transitions between sensitivity states.
- Alternating drug treatments targeting different cell death pathways can overcome resistance and improve therapeutic outcomes in cancer.
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