Journal article

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

Arcadi Cipponi, David L Goode, Justin Bedo, Mark J McCabe, Marina Pajic, David R Croucher, Alvaro Gonzalez Rajal, 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 Keerthikumar Show all

Science | American Association for the Advancement of Science | Published : 2020

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 d..

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Grants

Awarded by Australian National Health and Medical Research Council (NHMRC)


Awarded by NHMRC


Awarded by Cancer Australia


Funding Acknowledgements

This research was supported by the Australian National Health and Medical Research Council (NHMRC project grant no. 1088353 to D.M.T., A.C. and D.L.G.) and by the Girgensohn Foundation (A.C.) In vivo studies were supported by NHMRC 1162860, NHMRC 1162556, and Cancer Australia 1143699 project grants (M.P.). J.B. was supported by the Stafford Fox Centenary Fellowship in Bionformatics and Computational Biology of Rare Cancers.