Intermittent treatment of BRAF <sup>V600E</sup> melanoma cells delays resistance by adaptive resensitization to drug rechallenge-Reference-Cited by-同舟云学术

Intermittent treatment of BRAF ^V600E melanoma cells delays resistance by adaptive resensitization to drug rechallenge

Published:2022-03-15 Issue:12 Volume:119 Page:
ISSN:0027-8424
Container-title:Proceedings of the National Academy of Sciences
language:en
Short-container-title:Proc. Natl. Acad. Sci. U.S.A.

Author:

Kavran Andrew J.¹²,Stuart Scott A.¹,Hayashi Kristyn R.¹,Basken Joel M.¹,Brandhuber Barbara J.³,Ahn Natalie G.¹²^ORCID

Affiliation:

1. Department of Biochemistry, University of Colorado, Boulder, CO 80309

2. BioFrontiers Institute, University of Colorado, Boulder, CO 80309

3. Structural Biology, Array BioPharma, Boulder, CO 80301

Abstract

Significance Preclinical studies of metastatic melanoma treated with targeted therapeutics have suggested that alternating periods of treatment and withdrawal might delay the onset of resistance. This has been attributed to drug addiction, where cells lose fitness upon drug removal due to the resulting hyperactivation of mitogen-activated protein (MAP) kinase signaling. This study presents evidence that the intermittent treatment response can also be explained by the resensitization of cells following drug removal and enhanced cell loss upon drug rechallenge. Resensitization is accompanied by adaptive transcriptomic switching and occurs despite the sustained expression of resistance genes throughout the intermittent treatment.

Funder

HHS | National Institutes of Health

National Science Foundation

Array BioPharma

ALSAM/University of Colorado

HHS | NIH | National Institute of General Medical Sciences

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Link

https://pnas.org/doi/pdf/10.1073/pnas.2113535119

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