MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer.
Adaptation, Physiological
/ genetics
Antineoplastic Agents
/ pharmacology
Cell Line, Tumor
DNA Repair
/ genetics
Drug Resistance, Neoplasm
/ genetics
Genetic Fitness
Genome-Wide Association Study
Humans
Mutagenesis
Neoplasms
/ drug therapy
Selection, Genetic
Signal Transduction
TOR Serine-Threonine Kinases
/ genetics
Journal
Science (New York, N.Y.)
ISSN: 1095-9203
Titre abrégé: Science
Pays: United States
ID NLM: 0404511
Informations de publication
Date de publication:
05 06 2020
05 06 2020
Historique:
received:
11
09
2018
revised:
09
11
2019
accepted:
10
04
2020
entrez:
6
6
2020
pubmed:
6
6
2020
medline:
23
6
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32499442
pii: 368/6495/1127
doi: 10.1126/science.aau8768
doi:
Substances chimiques
Antineoplastic Agents
0
MTOR protein, human
EC 2.7.1.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1127-1131Informations de copyright
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.