MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer

• Published in: Science (American Association for the Advancement of Science) Vol. 368; no. 6495; pp. 1127 - 1131
• Main Authors: Cipponi, Arcadi, Goode, David L., Bedo, Justin, McCabe, Mark J., Pajic, Marina, Croucher, David R., Rajal, Alvaro Gonzalez, Junankar, Simon R., Saunders, Darren N., Lobachevsky, Pavel, Papenfuss, Anthony T., Nessem, Danielle, Nobis, Max, Warren, Sean C., Timpson, Paul, Cowley, Mark, Vargas, Ana C., Qiu, Min R., Generali, Daniele G., Keerthikumar, Shivakumar, Nguyen, Uyen, Corcoran, Niall M., Long, Georgina V., Blay, Jean-Yves, Thomas, David M.
• Format: Journal Article
• Language: English
• Published: Washington The American Association for the Advancement of Science 05-06-2020
• Subjects: Adaptation; Antibiotics; Cancer; Deoxyribonucleic acid; DNA; DNA repair; Drug resistance; Evolution; Evolution & development; Fitness; Genetic diversity; Genomes; Microorganisms; Mutagenesis; Mutation; Normalizing; Rapamycin; Reproductive fitness; Signal transduction; Signaling; Target recognition; TOR protein
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aau8768

How cancer cells adapt to stress
Bacteria adapt to harsh conditions such as antibiotic exposure by acquiring new mutations, a process called stress-induced mutagenesis. Cipponi
et al.
investigated whether similar programs of mutagenesis play a role in the response of cancer cells to targeted therapies. Using in vitro models of intense drug selection and genome-wide functional screens, the authors found evidence for an analogous process in cancer and showed that it is regulated by the mammalian target of rapamycin (mTOR) signaling pathway. This pathway appears to mediate a stress-related switch to error-prone DNA repair, resulting in the generation of mutations that facilitate the emergence of drug resistance.
Science
, this issue p.
1127
An evolutionarily conserved program of adaptive mutagenesis accelerates drug resistance in human cancers.
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.