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Rapidly induced drug adaptation mediates escape from BRAF inhibition in single melanoma cells

Chen Yang, View ORCID ProfileChengzhe Tian, Timothy E. Hoffman, Nicole K. Jacobsen, View ORCID ProfileSabrina L. Spencer
doi: https://doi.org/10.1101/2020.03.15.992982
Chen Yang
1Department of Biochemistry and BioFrontiers Institute, University of Colorado-Boulder, Boulder, CO 80303 USA
2Department of Molecular, Cellular, and Developmental Biology, University of Colorado-Boulder, Boulder, CO 80303 USA
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Chengzhe Tian
1Department of Biochemistry and BioFrontiers Institute, University of Colorado-Boulder, Boulder, CO 80303 USA
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Timothy E. Hoffman
1Department of Biochemistry and BioFrontiers Institute, University of Colorado-Boulder, Boulder, CO 80303 USA
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Nicole K. Jacobsen
1Department of Biochemistry and BioFrontiers Institute, University of Colorado-Boulder, Boulder, CO 80303 USA
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Sabrina L. Spencer
1Department of Biochemistry and BioFrontiers Institute, University of Colorado-Boulder, Boulder, CO 80303 USA
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  • ORCID record for Sabrina L. Spencer
  • For correspondence: sabrina.spencer@colorado.edu
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Abstract

Despite increasing numbers of effective anti-cancer therapies, successful treatment is limited by the development of drug resistance. While the contribution of genetic factors to drug resistance is undeniable, little is known about how drug-sensitive cells first evade drug action to proliferate in drug. Here we track the response of thousands of single melanoma cells to BRAF inhibitors and show that a subset escapes drug within the first 3 days of treatment. Cell-cycle re-entry occurs via a non-genetic mechanism involving activation of mTORC1 and ATF4, validated in cultures of patient biopsies. These escapees cycle periodically in drug, incur significant DNA damage, and out-proliferate non-escapees over extended treatment. Our work reveals a mutagenesis-prone, expanding subpopulation of early drug escapees that may seed development of permanent drug resistance.

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Posted March 17, 2020.
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Rapidly induced drug adaptation mediates escape from BRAF inhibition in single melanoma cells
Chen Yang, Chengzhe Tian, Timothy E. Hoffman, Nicole K. Jacobsen, Sabrina L. Spencer
bioRxiv 2020.03.15.992982; doi: https://doi.org/10.1101/2020.03.15.992982
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Rapidly induced drug adaptation mediates escape from BRAF inhibition in single melanoma cells
Chen Yang, Chengzhe Tian, Timothy E. Hoffman, Nicole K. Jacobsen, Sabrina L. Spencer
bioRxiv 2020.03.15.992982; doi: https://doi.org/10.1101/2020.03.15.992982

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