1. MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer.
- Author
-
Cipponi A, Goode DL, Bedo J, McCabe MJ, Pajic M, Croucher DR, Rajal AG, Junankar SR, Saunders DN, Lobachevsky P, Papenfuss AT, Nessem D, Nobis M, Warren SC, Timpson P, Cowley M, Vargas AC, Qiu MR, Generali DG, Keerthikumar S, Nguyen U, Corcoran NM, Long GV, Blay JY, and Thomas DM
- Subjects
- Antineoplastic Agents therapeutic use, Cell Line, Tumor, DNA Repair genetics, Genetic Fitness, Genome-Wide Association Study, Humans, Selection, Genetic, Signal Transduction, TOR Serine-Threonine Kinases genetics, Adaptation, Physiological genetics, Antineoplastic Agents pharmacology, Drug Resistance, Neoplasm genetics, Mutagenesis, Neoplasms drug therapy, Neoplasms genetics, TOR Serine-Threonine Kinases metabolism
- 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., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2020
- Full Text
- View/download PDF