PMID- 18199554
OWN - NLM
STAT- MEDLINE
DCOM- 20080214
LR  - 20181201
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 68
IP  - 2
DP  - 2008 Jan 15
TI  - Impact of common epidermal growth factor receptor and HER2 variants on receptor 
      activity and inhibition by lapatinib.
PG  - 571-9
LID - 10.1158/0008-5472.CAN-07-2404 [doi]
AB  - The goal of this study was to characterize the effects of non-small cell lung 
      carcinoma (NSCLC)-associated mutations in epidermal growth factor receptor 
      (EGFR/ErbB1) and HER2 (ErbB2) on interactions with the dual tyrosine kinase 
      inhibitor lapatinib. Biochemical studies show that commonly observed variants of 
      EGFR [G719C, G719S, L858R, L861Q, and Delta746-750 (del15)] are enzyme 
      activating, increasing the tyrosine kinase V(max) and increasing the K(m)((app)) 
      for ATP. The point mutations G719C and L861Q had minor effects on lapatinib 
      K(i)s, whereas EGFR mutations L858R and del15 had a higher K(i) for lapatinib 
      than wild-type EGFR. Structural analysis of wild-type EGFR-lapatinib complexes 
      and modeling of the EGFR mutants were consistent with these data, suggesting that 
      loss of structural flexibility and possible stabilization of the active-like 
      conformation could interfere with lapatinib binding, particularly to the EGFR 
      deletion mutants. Furthermore, EGFR deletion mutants were relatively resistant to 
      lapatinib-mediated inhibition of receptor autophosphorylation in recombinant 
      cells expressing the variants, whereas EGFR point mutations had a modest or no 
      effect. Of note, EGFR T790M, a receptor variant found in patients with 
      gefitinib-resistant NSCLC, was also resistant to lapatinib-mediated inhibition of 
      receptor autophosphorylation. Two HER2 insertional variants found in NSCLC were 
      less sensitive to lapatinib inhibition than two HER2 point mutants. The effects 
      of lapatinib on the proliferation of human NSCLC tumor cell lines expressing 
      wild-type or variant EGFR and HER2 cannot be explained solely on the basis of the 
      biochemical activity or receptor autophosphorylation in recombinant cells. These 
      data suggest that cell line genetic heterogeneity and/or multiple determinants 
      modulate the role played by EGFR/HER2 in regulating cell proliferation.
FAU - Gilmer, Tona M
AU  - Gilmer TM
AD  - Department of Translational Medicine, GlaxoSmithKline, 5 Moore Drive, Research 
      Triangle Park, NC 27709, USA. tona.m.gilmer@gsk.com
FAU - Cable, Louann
AU  - Cable L
FAU - Alligood, Krystal
AU  - Alligood K
FAU - Rusnak, David
AU  - Rusnak D
FAU - Spehar, Glenn
AU  - Spehar G
FAU - Gallagher, Kathleen T
AU  - Gallagher KT
FAU - Woldu, Ermias
AU  - Woldu E
FAU - Carter, H Luke
AU  - Carter HL
FAU - Truesdale, Anne T
AU  - Truesdale AT
FAU - Shewchuk, Lisa
AU  - Shewchuk L
FAU - Wood, Edgar R
AU  - Wood ER
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Mutant Proteins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinazolines)
RN  - 0VUA21238F (Lapatinib)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - S65743JHBS (Gefitinib)
SB  - IM
MH  - Animals
MH  - CHO Cells
MH  - Carcinoma, Non-Small-Cell Lung/enzymology/genetics
MH  - Cell Proliferation/drug effects
MH  - Cricetinae
MH  - Cricetulus
MH  - ErbB Receptors/*antagonists & inhibitors/chemistry/*genetics/*metabolism
MH  - Gefitinib
MH  - *Genes, erbB-2
MH  - Humans
MH  - Lapatinib
MH  - Lung Neoplasms/enzymology/genetics
MH  - Models, Molecular
MH  - Mutant Proteins/metabolism
MH  - Phosphorylation/drug effects
MH  - Polymorphism, Single Nucleotide/*physiology
MH  - Protein Binding
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Quinazolines/*pharmacology
MH  - Receptor, ErbB-2/*antagonists & inhibitors/chemistry/*metabolism
MH  - Structure-Activity Relationship
MH  - Tumor Cells, Cultured
EDAT- 2008/01/18 09:00
MHDA- 2008/02/15 09:00
CRDT- 2008/01/18 09:00
PHST- 2008/01/18 09:00 [pubmed]
PHST- 2008/02/15 09:00 [medline]
PHST- 2008/01/18 09:00 [entrez]
AID - 68/2/571 [pii]
AID - 10.1158/0008-5472.CAN-07-2404 [doi]
PST - ppublish
SO  - Cancer Res. 2008 Jan 15;68(2):571-9. doi: 10.1158/0008-5472.CAN-07-2404.