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

yang, c.; Tian, C.; Hoffman, T. E.; Jacobsen, N. K.; Spencer, S. L.

doi:10.1101/2020.03.15.992982

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bioRxiv · 10.1101/2020.03.15.992982

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

yang, c.·Tian, C.·Hoffman, T. E.·Jacobsen, N. K.·Spencer, S. L.

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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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yang, c., Tian, C., Hoffman, T. E., Jacobsen, N. K., Spencer, S. L.. 2020-03-17. Rapidly induced drug adaptation mediates escape from BRAF inhibition in single melanoma cells. https://doi.org/10.1101/2020.03.15.992982

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