Cellular adaptation to cancer therapy along a resistance continuum

Area of Science:

• Oncology
• Cancer Biology
• Systems Biology

Background:

• Precision oncology offers targeted therapies, but drug resistance limits efficacy.
• Non-genetic plasticity contributes to both transient drug tolerance and stable resistance.
• The dynamics of cell-state transitions during therapy adaptation are not well understood.

Purpose of the Study:

• To investigate the longitudinal dynamics of cell-state transitions in response to cancer therapies.
• To define a systems-level framework for understanding the development of drug resistance.
• To identify therapeutic vulnerabilities arising from adaptive cellular changes.

Main Methods:

• Longitudinal, systems-level framework to track cell-state transitions.
• Analysis of gene expression programs and epigenetic modifications.
• Systematic genetic perturbations to identify metabolic dependencies.

Main Results:

• Drug resistance emerges via trajectories of cell-state transitions, termed the 'resistance continuum'.
• Cellular adaptation involves stepwise gene expression assembly, epigenetic reinforcement, and metabolic reprogramming.
• Epithelial-to-mesenchymal transition and stemness programs facilitate adaptation but are not full resistance mechanisms.
• Acquisition of metabolic dependencies reveals potential therapeutic targets.

Conclusions:

• The 'resistance continuum' model explains dynamic cellular adaptation to cancer therapies.
• Phenotypic plasticity, stress adaptation, and metabolic reprogramming are key to resistance.
• Targeting adaptive cell-state transitions with complementary therapies is a promising strategy.