Mapping kinase domain resistance mechanisms for the MET receptor tyrosine kinase via deep mutational scanning.
bioRxiv
; 2024 Jul 18.
Article
em En
| MEDLINE
| ID: mdl-39071407
ABSTRACT
Mutations in the kinase and juxtamembrane domains of the MET Receptor Tyrosine Kinase are responsible for oncogenesis in various cancers and can drive resistance to MET-directed treatments. Determining the most effective inhibitor for each mutational profile is a major challenge for MET-driven cancer treatment in precision medicine. Here, we used a deep mutational scan (DMS) of ~5,764 MET kinase domain variants to profile the growth of each mutation against a panel of 11 inhibitors that are reported to target the MET kinase domain. We identified common resistance sites across type I, type II, and type I ½ inhibitors, unveiled unique resistance and sensitizing mutations for each inhibitor, and validated non-cross-resistant sensitivities for type I and type II inhibitor pairs. We augment a protein language model with biophysical and chemical features to improve the predictive performance for inhibitor-treated datasets. Together, our study demonstrates a pooled experimental pipeline for identifying resistance mutations, provides a reference dictionary for mutations that are sensitized to specific therapies, and offers insights for future drug development.
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1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
BioRxiv
Ano de publicação:
2024
Tipo de documento:
Article