Combining Mutational Signatures, Clonal Fitness, and Drug Affinity to Define Drug-Specific Resistance Mutations in Cancer. Issue 11 (15th November 2018)

• Record Type: Journal Article
• Authors: Kaserer, Teresa; Blagg, Julian
• Is Part Of: Cell chemical biology. Volume 25:Issue 11(2018)
• Page Start: 1359
• Page End: 1371.e2
• Publication Date: 2018-11-15
• Subjects: drug resistance -- resistance hotspot -- clonal fitness -- mutation signature -- targeted cancer drugs; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2018.07.013
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: The emergence of mutations that confer resistance to molecularly targeted therapeutics is dependent upon the effect of each mutation on drug affinity for the target protein, the clonal fitness of cells harboring the mutation, and the probability that each variant can be generated by DNA codon base mutation. We present a computational workflow that combines these three factors to identify mutations likely to arise upon drug treatment in a particular tumor type. The Osprey-based workflow is validated using a comprehensive dataset of ERK2 mutations and is applied to small-molecule drugs and/or therapeutic antibodies targeting KIT, EGFR, Abl, and ALK. We identify major clinically observed drug-resistant mutations for drug-target pairs and highlight the potential to prospectively identify probable drug resistance mutations. Graphical Abstract: Highlights: Drug affinity, clonal fitness, and mutation signatures define resistant mutations We report a computational work flow to identify drug-resistant hotspot mutations A comprehensive ERK2 resistance mutation dataset is used to validate the work flow Clinically relevant, drug-resistant mutations are identified Abstract : Resistance to targeted cancer drugs is a major challenge in therapy. Kaserer and Blagg report a computational approach to prospectively identify and prioritize clinically relevant drug-resistant mutations; it facilitates improved patient monitoring for the emergence of resistance and the timely discovery of durable treatment options.