MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer
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 inte...
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| Published in: | Science (American Association for the Advancement of Science) Vol. 368; no. 6495; pp. 1127 - 1131 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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05-06-2020
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| Abstract | 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. |
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| AbstractList | How cancer cells adapt to stressBacteria 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. 1127In 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. 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. |
| Author | Nobis, Max Papenfuss, Anthony T. Blay, Jean-Yves Warren, Sean C. Pajic, Marina Nguyen, Uyen Lobachevsky, Pavel Rajal, Alvaro Gonzalez Nessem, Danielle Keerthikumar, Shivakumar Cipponi, Arcadi Bedo, Justin Generali, Daniele G. Timpson, Paul Saunders, Darren N. Corcoran, Niall M. Junankar, Simon R. Vargas, Ana C. McCabe, Mark J. Qiu, Min R. Thomas, David M. Croucher, David R. Goode, David L. Cowley, Mark Long, Georgina V. |
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Mark J. orcidid: 0000-0003-1346-6419 surname: McCabe fullname: McCabe, Mark J. organization: St. Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia., Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia – sequence: 5 givenname: Marina orcidid: 0000-0002-3871-3829 surname: Pajic fullname: Pajic, Marina organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia., St. Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia – sequence: 6 givenname: David R. orcidid: 0000-0003-4965-8674 surname: Croucher fullname: Croucher, David R. organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia., St. Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia – sequence: 7 givenname: Alvaro Gonzalez orcidid: 0000-0002-9230-0339 surname: Rajal fullname: Rajal, Alvaro 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NSW, Australia., St. Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia – sequence: 15 givenname: Paul surname: Timpson fullname: Timpson, Paul organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia., St. Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia – sequence: 16 givenname: Mark orcidid: 0000-0002-9519-5714 surname: Cowley fullname: Cowley, Mark organization: St. Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia., Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia – sequence: 17 givenname: Ana C. surname: Vargas fullname: Vargas, Ana C. organization: Douglass Hanly Moir Pathology, Turramurra, NSW, Australia – sequence: 18 givenname: Min R. surname: Qiu fullname: Qiu, Min R. organization: St. Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia., 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organization: Division of Urology, Royal Melbourne Hospital, Parkville, VIC, Australia., Department of Urology, Peninsula Health, Frankston, VIC, Australia., Department of Surgery, University of Melbourne, VIC, Australia – sequence: 23 givenname: Georgina V. orcidid: 0000-0001-8894-3545 surname: Long fullname: Long, Georgina V. organization: Melanoma Institute Australia, Wollstonecraft, NSW, Australia., The University of Sydney, Sydney, NSW, Australia., Royal North Shore Hospital and Mater Hospital, Sydney, NSW, Australia., Crown Princess Mary Cancer Centre Westmead Hospital, Sydney, NSW, Australia – sequence: 24 givenname: Jean-Yves orcidid: 0000-0001-7190-120X surname: Blay fullname: Blay, Jean-Yves organization: Centre Leon Berard and Université Claude Bernard Lyon, Lyon, France., UNICANCER, Paris, France – sequence: 25 givenname: David M. orcidid: 0000-0002-2527-5428 surname: Thomas fullname: Thomas, David M. organization: The Kinghorn Cancer Centre, Garvan Institute of Medical 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| SubjectTerms | 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 |
| Title | MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer |
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