2. Academic Validation
  3. Cellular adaptation to cancer therapy along a resistance continuum

Cellular adaptation to cancer therapy along a resistance continuum

  • Nature. 2024 Jul;631(8022):876-883. doi: 10.1038/s41586-024-07690-9.
Gustavo S França 1 2,  Maayan Baron # 1,  Benjamin R King # 2 3,  Jozef P Bossowski # 4,  Alicia Bjornberg # 5,  Maayan Pour # 1 2,  Anjali Rao # 1,  Ayushi S Patel # 1 2,  Selim Misirlioglu 6,  Dalia Barkley 1,  Kwan Ho Tang 6 7,  Igor Dolgalev 8,  Deborah A Liberman 1 2,  Gal Avital 1,  Felicia Kuperwaser 1 2,  Marta Chiodin 1,  Douglas A Levine 6 9,  Thales Papagiannakopoulos 6 3,  Andriy Marusyk 5,  Timothée Lionnet 2 10,  Itai Yanai 11 12 13 14
Affiliations

Affiliations

  • 1 Institute for Computational Medicine, NYU Grossman School of Medicine, New York, NY, USA.
  • 2 Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY, USA.
  • 3 Bristol-Myers Squibb Company, Lawrenceville, NJ, USA.
  • 4 Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA.
  • 5 Department of Cancer Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
  • 6 Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA.
  • 7 Translational Medicine, Oncology R&D, AstraZeneca, Boston, MA, USA.
  • 8 Applied Bioinformatics Laboratories, NYU Grossman School of Medicine, New York, NY, USA.
  • 9 Merck & Co., Rahway, NJ, USA.
  • 10 Department of Cell Biology, NYU Grossman School of Medicine, New York, NY, USA.
  • 11 Institute for Computational Medicine, NYU Grossman School of Medicine, New York, NY, USA. itai.yanai@nyulangone.org.
  • 12 Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY, USA. itai.yanai@nyulangone.org.
  • 13 Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA. itai.yanai@nyulangone.org.
  • 14 Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA. itai.yanai@nyulangone.org.
  • # Contributed equally.
PMID: 38987605 DOI: 10.1038/s41586-024-07690-9
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.

Figures
Products