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MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer
Arcadi Cipponi1,2, David L Goode3,4, Justin Bedo5,6,7
1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia. a.cipponi@garvan.org.au d.thomas@garvan.org.au.
Abstract:
In microorganisms, evolutionarily conserved mechanisms facilitate adaptation to harsh conditions through stress-induced mutagenesis (SIM). Analogous processes may underpin progression and therapeutic failure in human cancer. We describe SIM in multiple in vitro and in vivo models of human cancers under nongenotoxic drug selection, paradoxically enhancing adaptation at a competing intrinsic fitness cost. A genome-wide approach identified the mechanistic target of rapamycin (MTOR) as a stress-sensing rheostat mediating SIM across multiple cancer types and conditions. These observations are consistent with a two-phase model for drug resistance, in which an initially rapid expansion of genetic diversity is counterbalanced by an intrinsic fitness penalty, subsequently normalizing to complete adaptation under the new conditions. This model suggests synthetic lethal strategies to minimize resistance to anticancer therapy.
Insights
Stress-induced mutagenesis (SIM) helps microbes adapt to harsh conditions. In human cancers, SIM drives drug resistance through a two-phase adaptation process involving MTOR, suggesting new therapeutic strategies.
Area of Science:
- Cancer Biology
- Genetics
- Evolutionary Biology
Background:
- Stress-induced mutagenesis (SIM) is a conserved mechanism for microbial adaptation.
- Similar processes may contribute to cancer progression and treatment failure.
Purpose of the Study:
- To investigate the role of SIM in human cancer drug resistance.
- To identify the molecular mechanisms mediating SIM in cancer.
- To propose a model for drug resistance and potential therapeutic interventions.
Main Methods:
- Utilized in vitro and in vivo cancer models.
- Applied nongenotoxic drug selection.
- Conducted genome-wide analysis.
- Investigated the mechanistic target of rapamycin (MTOR) pathway.
Main Results:
- SIM enhances cancer adaptation under drug selection, despite an intrinsic fitness cost.
- MTOR acts as a stress-sensing rheostat regulating SIM across various cancer types.
- A two-phase model of drug resistance was observed: initial diversity expansion followed by adaptation.
Conclusions:
- SIM is a significant factor in cancer drug resistance.
- MTOR is a key mediator of SIM in cancer.
- Targeting MTOR or employing synthetic lethal strategies may overcome drug resistance.
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