RT Journal Article
SR Electronic
T1 Drug-induced adaptation along a resistance continuum in cancer cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.06.21.496830
DO 10.1101/2022.06.21.496830
A1 Gustavo S. França
A1 Maayan Baron
A1 Maayan Pour
A1 Benjamin R. King
A1 Anjali Rao
A1 Selim Misirlioglu
A1 Dalia Barkley
A1 Igor Dolgalev
A1 Kwan Ho-Tang
A1 Gal Avital
A1 Felicia Kuperwaser
A1 Ayushi Patel
A1 Douglas A. Levine
A1 Timothee Lionnet
A1 Itai Yanai
YR 2022
UL http://biorxiv.org/content/early/2022/06/25/2022.06.21.496830.abstract
AB Advancements in rational drug design over the past decades have consistently produced new cancer therapies, but such treatments are inevitably countered through an adaptive process that fosters therapy resistance. Malignant cells achieve drug resistance through intrinsic and acquired mechanisms, rooted in genetic and non-genetic determinants. In particular, recent work has highlighted the role of intrinsic cellular heterogeneity in the emergence of transient drug-tolerant persister cells that survive drug treatment, as well as non-genetically driven cell plasticity toward stable resistance. However, these models do not account for the role of dose and treatment duration as extrinsic forces in eliciting cancer cell adaptation. Here, we show that these two components together drive the resistance of ovarian cancer cells to targeted therapy along a trajectory of cellular adaptation, that we denote the ‘resistance continuum’. We report that gradual dose exposure and prolonged treatment promote a continuous increase in fitness, and show that this process is mediated by evolving transcriptional, epigenetic and genetic changes that promote multiple cell state transitions. The resistance continuum is underpinned by the assembly of gene expression programs and epigenetically reinforced stress response regulation. Using both in vivo and in vitro models, we found that this process involves widespread reprogramming of cell survival pathways, including interferon response, lineage reprogramming, metabolic rewiring and oxidative stress regulation. Together, the resistance continuum reveals the dynamic nature of cellular adaptation, and carries implications for cancer therapies, as initial exposure to lower doses primes cells over time for increased resistance to higher doses. Beyond cancer, such continuous adaptation exposes a basic aspect of cellular plasticity, which may also be deployed in other biological systems such as development, immune response and host-pathogen interactions.Competing Interest StatementThe authors have declared no competing interest.