Discernment between candidate mechanisms for KRAS G13D colorectal cancer sensitivity to EGFR inhibitors. Cell Commun Signal 2020 Nov 05;18(1):179
Date
11/07/2020Pubmed ID
33153459Pubmed Central ID
PMC7643456DOI
10.1186/s12964-020-00645-3Scopus ID
2-s2.0-85095115047 (requires institutional sign-in at Scopus site) 6 CitationsAbstract
Phase three clinical trial evidence suggests that colorectal cancers with the KRAS G13D mutation may benefit from EGFR inhibitors, like cetuximab, in contrast to the other most common KRAS mutations. A mechanism to explain why this mutation behaves differently from other KRAS mutations had long been lacking. Two recent studies have reproduced KRAS G13D specific sensitivity to cetuximab in cellular models, and both have implicated the tumor suppressor NF1 as a critical variable in determining sensitivity and resistance. One study proposes a mechanism that focuses on the inhibition of active, GTP-bound wild-type RAS, which is proposed to occur to a greater extent in KRAS G13D tumors due to the inability of KRAS G13D to bind NF1 well. The other study suggests NF1 can convert GTP-bound KRAS G13D to inactive, GDP-bound KRAS G13D. Here, we report an inability to reproduce cellular and biophysical studies that suggested NF1 has strong GTPase activity on KRAS G13D. We also report additional data that further suggests only WT RAS-GTP levels are reduced with EGFR inhibition and that KRAS G13D is impaired in binding to NF1. These new experiments further support a mechanism in which cetuximab inhibits wild-type (HRAS and NRAS) signals in KRAS G13D colorectal cancers. Video Abstract.
Author List
McFall T, Schomburg NK, Rossman KL, 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
Biophysical PhenomenaColorectal Neoplasms
ErbB Receptors
Fluorescence Resonance Energy Transfer
HCT116 Cells
HEK293 Cells
Humans
Mutant Proteins
Mutation
Neurofibromin 1
Protein Binding
Protein Kinase Inhibitors
Proto-Oncogene Proteins p21(ras)
