Cellular adaptation to cancer therapy along a resistance continuum

Gustavo S. França, Maayan Baron, Benjamin R. King, Jozef P. Bossowski, Alicia Bjornberg, Maayan Pour, Anjali Rao, Ayushi S. Patel, Selim Misirlioglu, Dalia Barkley, Kwan Ho Tang, Igor Dolgalev, Deborah A. Liberman, Gal Avital, Felicia Kuperwaser, Marta Chiodin, Douglas A. Levine, Thales Papagiannakopoulos, Andriy Marusyk, Timothée Lionnet and Itai Yanai ()
Additional contact information
Gustavo S. França: NYU Grossman School of Medicine
Maayan Baron: NYU Grossman School of Medicine
Benjamin R. King: NYU Grossman School of Medicine
Jozef P. Bossowski: NYU Grossman School of Medicine
Alicia Bjornberg: H. Lee Moffitt Cancer Center and Research Institute
Maayan Pour: NYU Grossman School of Medicine
Anjali Rao: NYU Grossman School of Medicine
Ayushi S. Patel: NYU Grossman School of Medicine
Selim Misirlioglu: NYU Grossman School of Medicine
Dalia Barkley: NYU Grossman School of Medicine
Kwan Ho Tang: NYU Grossman School of Medicine
Igor Dolgalev: NYU Grossman School of Medicine
Deborah A. Liberman: NYU Grossman School of Medicine
Gal Avital: NYU Grossman School of Medicine
Felicia Kuperwaser: NYU Grossman School of Medicine
Marta Chiodin: NYU Grossman School of Medicine
Douglas A. Levine: NYU Grossman School of Medicine
Thales Papagiannakopoulos: NYU Grossman School of Medicine
Andriy Marusyk: H. Lee Moffitt Cancer Center and Research Institute
Timothée Lionnet: NYU Grossman School of Medicine
Itai Yanai: NYU Grossman School of Medicine

Nature, 2024, vol. 631, issue 8022, 876-883

Abstract: Abstract Advancements in precision oncology over the past decades have led to new therapeutic interventions, but the efficacy of such treatments is generally limited by an adaptive process that fosters drug resistance1. In addition to genetic mutations2, recent research has identified a role for non-genetic plasticity in transient drug tolerance3 and the acquisition of stable resistance4,5. However, the dynamics of cell-state transitions that occur in the adaptation to cancer therapies remain unknown and require a systems-level longitudinal framework. Here we demonstrate that resistance develops through trajectories of cell-state transitions accompanied by a progressive increase in cell fitness, which we denote as the ‘resistance continuum’. This cellular adaptation involves a stepwise assembly of gene expression programmes and epigenetically reinforced cell states underpinned by phenotypic plasticity, adaptation to stress and metabolic reprogramming. Our results support the notion that epithelial-to-mesenchymal transition or stemness programmes—often considered a proxy for phenotypic plasticity—enable adaptation, rather than a full resistance mechanism. Through systematic genetic perturbations, we identify the acquisition of metabolic dependencies, exposing vulnerabilities that can potentially be exploited therapeutically. The concept of the resistance continuum highlights the dynamic nature of cellular adaptation and calls for complementary therapies directed at the mechanisms underlying adaptive cell-state transitions.

Date: 2024
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DOI: 10.1038/s41586-024-07690-9

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