Drug response to HER2 gatekeeper T798M mutation in HER2-positive breast cancer.
Amino Acids
; 48(2): 487-97, 2016 Feb.
Article
in En
| MEDLINE
| ID: mdl-26439378
ABSTRACT
The gatekeeper T798M mutation in HER2 kinase domain has been observed to considerably shift drug sensitivity to HER2 in breast cancer therapy. Here, drug response of clinical tyrosine kinase inhibitors (TKIs) to the mutation was profiled using a synthetic biology protocol. It was found that TKIs can be grouped into three classes in terms of their response behavior to T798M mutation class I inhibitors exhibit drug resistance upon the mutation, such as lapatinib, TAK-285 and AEE788; class II inhibitors are insensitive to the mutation, such as erlotinib and gefitinib; and class III inhibitors can be sensitized by the mutation, such as staurosporine. However, kinetic study indicated that the mutation has only a modest effect on the binding of substrate ATP to HER2. Binding free energy analysis revealed that the drug response is primarily determined by direct interaction between the kinase and inhibitors, but not by indirect kinase interaction with competitive ATP. This is different to the molecular mechanism of "generic" drug resistance conferring from EGFR gatekeeper T790M mutation, which is caused by increased ATP affinity upon the mutation. Structural analysis of kinase-inhibitor complexes unraveled that HER2 T798M mutation induces significant steric hindrance to class I inhibitors, but can establish additional nonbonded interactions for class III inhibitors.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Breast Neoplasms
/
Receptor, ErbB-2
/
Protein Kinase Inhibitors
/
Antineoplastic Agents
Type of study:
Guideline
Limits:
Female
/
Humans
Language:
En
Journal:
Amino Acids
Journal subject:
BIOQUIMICA
Year:
2016
Document type:
Article
Affiliation country:
China
Publication country:
AT
/
AUSTRIA
/
ÁUSTRIA