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

• DOI: 10.1126/science.aau8768
• Publication Date: 2020-06-04T23:05:21Z
• Authors: Arcadi Cipponi; David L. Goode; Justin Bedo; Mark J. McCabe; Marina Pajic; David R. Croucher; Alvaro Gonzalez R...; Simon R. Junankar; Darren N. Saunders; Pavel Lobachevsky; Anthony T. Papenfuss; Danielle Nessem; Max Nobis; Sean C. Warren; Paul Timpson; Mark Cowley; Ana C. Vargas; Min R. Qiu; Daniele G. Generali; Shivakumar Keerth...; Uyen Nguyen; Niall M. Corcoran; Georgina V. Long; Jean-Yves Blay; David M. Thomas
• Keywords: MTOR; cancer cells; mutations; targeted therapies; 0303 health sciences; DNA Repair; MTOR; TOR Serine-Threonine Kinases; Antineoplastic Agents; Adaptation, Physiological; targeted therapies; 3. Good health; 03 medical and health sciences; Drug Resistance, Neoplasm; Mutagenesis; Cell Line, Tumor; Neoplasms; Humans; Genetic Fitness; mutation; Selection, Genetic; cancer cell; Genome-Wide Association Study; Signal Transduction

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