MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer.
Science
; 368(6495): 1127-1131, 2020 06 05.
Article
em En
| MEDLINE
| ID: mdl-32499442
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.
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Base de dados:
MEDLINE
Assunto principal:
Adaptação Fisiológica
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Mutagênese
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Resistencia a Medicamentos Antineoplásicos
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Serina-Treonina Quinases TOR
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Neoplasias
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Antineoplásicos
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article