Identification of RAS mutant biomarkers for EGFR inhibitor sensitivity using a systems biochemical approach. Cell Rep 2021 Dec 14;37(11):110096
Date
12/16/2021Pubmed ID
34910921Pubmed Central ID
PMC8867612DOI
10.1016/j.celrep.2021.110096Scopus ID
2-s2.0-85121146579 (requires institutional sign-in at Scopus site) 6 CitationsAbstract
Mutations can be important biomarkers that influence the selection of specific cancer treatments. We recently combined mathematical modeling of RAS signaling network biochemistry with experimental cancer cell biology to determine why KRAS G13D is a biomarker for sensitivity to epidermal growth factor receptor (EGFR)-targeted therapies. The critical mechanistic difference between KRAS G13D and the other most common KRAS mutants is impaired binding to tumor suppressor Neurofibromin (NF1). Here, we hypothesize that impaired binding to NF1 is a "biophysical biomarker" that defines other RAS mutations that retain therapeutic sensitivity to EGFR inhibition. Both computational and experimental investigations support our hypothesis. By screening RAS mutations for this biophysical characteristic, we identify 10 additional RAS mutations that appear to be biomarkers for sensitivity to EGFR inhibition. Altogether, this work suggests that personalized medicine may benefit from migrating from gene-based and allele-based biomarker strategies to biomarkers based on biophysically defined subsets of mutations.
Author List
McFall T, Stites ECAuthor
Thomas Mcfall PhD Assistant Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Biomarkers, TumorColorectal Neoplasms
Drug Resistance, Neoplasm
ErbB Receptors
Humans
Mutation
Protein Kinase Inhibitors
Systems Analysis
Tumor Cells, Cultured
ras Proteins
