PMID- 17085664
OWN - NLM
STAT- MEDLINE
DCOM- 20070109
LR  - 20241219
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 12
IP  - 21
DP  - 2006 Nov 1
TI  - Novel D761Y and common secondary T790M mutations in epidermal growth factor 
      receptor-mutant lung adenocarcinomas with acquired resistance to kinase 
      inhibitors.
PG  - 6494-501
AB  - PURPOSE: In patients whose lung adenocarcinomas harbor epidermal growth factor 
      receptor (EGFR) tyrosine kinase domain mutations, acquired resistance to the 
      tyrosine kinase inhibitors (TKI) gefitinib (Iressa) and erlotinib (Tarceva) has 
      been associated with a second-site EGFR mutation, which leads to substitution of 
      methionine for threonine at position 790 (T790M). We aimed to elucidate the 
      frequency and nature of secondary EGFR mutations in patients with acquired 
      resistance to TKI monotherapy. EXPERIMENTAL DESIGN: Tumor cells from patients 
      with acquired resistance were examined for secondary EGFR kinase domain mutations 
      by molecular analyses. RESULTS: Eight of 16 patients (50% observed rate; 95% 
      confidence interval, 25-75%) had tumor cells with second-site EGFR mutations. 
      Seven mutations were T790M and one was a novel D761Y mutation found in a brain 
      metastasis. When combined with a drug-sensitive L858R mutation, the D761Y 
      mutation modestly reduced the sensitivity of mutant EGFR to TKIs in both 
      surrogate kinase and cell viability assays. In an autopsy case, the T790M 
      mutation was found in multiple visceral metastases but not in a brain lesion. 
      CONCLUSIONS: The T790M mutation is common in patients with acquired resistance. 
      The limited spectrum of TKI-resistant mutations in EGFR, which binds to erlotinib 
      in the active conformation, contrasts with a wider range of second-site mutations 
      seen with acquired resistance to imatinib, which binds to ABL and KIT, 
      respectively, in closed conformations. Collectively, our data suggest that the 
      type and nature of kinase inhibitor resistance mutations may be influenced by 
      both anatomic site and mode of binding to the kinase target.
FAU - Balak, Marissa N
AU  - Balak MN
AD  - Human Oncology and Pathogenesis Program, Thoracic Oncology Service, Varmus Lab, 
      Department of Pathology, Memorial Sloan-Kettering Cancer Center, Weill Medical 
      College of Cornell University, New York, New York 10021, USA.
FAU - Gong, Yixuan
AU  - Gong Y
FAU - Riely, Gregory J
AU  - Riely GJ
FAU - Somwar, Romel
AU  - Somwar R
FAU - Li, Allan R
AU  - Li AR
FAU - Zakowski, Maureen F
AU  - Zakowski MF
FAU - Chiang, Anne
AU  - Chiang A
FAU - Yang, Guangli
AU  - Yang G
FAU - Ouerfelli, Ouathek
AU  - Ouerfelli O
FAU - Kris, Mark G
AU  - Kris MG
FAU - Ladanyi, Marc
AU  - Ladanyi M
FAU - Miller, Vincent A
AU  - Miller VA
FAU - Pao, William
AU  - Pao W
LA  - eng
GR  - 5T32CA009207/CA/NCI NIH HHS/United States
GR  - K08-CA097980/CA/NCI NIH HHS/United States
GR  - R21-CA115051/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinazolines)
RN  - DA87705X9K (Erlotinib Hydrochloride)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - S65743JHBS (Gefitinib)
SB  - IM
CIN - Clin Cancer Res. 2007 Jun 1;13(11):3431; author reply 3431-2. doi: 
      10.1158/1078-0432.CCR-07-0070. PMID: 17545553
MH  - Adenocarcinoma/drug therapy/*genetics
MH  - Amino Acid Sequence
MH  - Antineoplastic Agents/therapeutic use
MH  - DNA Mutational Analysis
MH  - Drug Resistance, Neoplasm/*genetics
MH  - ErbB Receptors/chemistry/drug effects/*genetics
MH  - Erlotinib Hydrochloride
MH  - Gefitinib
MH  - Gene Dosage
MH  - Humans
MH  - In Situ Hybridization
MH  - Lung Neoplasms/drug therapy/*genetics
MH  - Molecular Sequence Data
MH  - Mutation
MH  - Neoplasm Metastasis/genetics
MH  - Protein Kinase Inhibitors/*therapeutic use
MH  - Protein Structure, Tertiary
MH  - Quinazolines/therapeutic use
MH  - Reverse Transcriptase Polymerase Chain Reaction
EDAT- 2006/11/07 09:00
MHDA- 2007/01/11 09:00
CRDT- 2006/11/07 09:00
PHST- 2006/11/07 09:00 [pubmed]
PHST- 2007/01/11 09:00 [medline]
PHST- 2006/11/07 09:00 [entrez]
AID - 12/21/6494 [pii]
AID - 10.1158/1078-0432.CCR-06-1570 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2006 Nov 1;12(21):6494-501. doi: 10.1158/1078-0432.CCR-06-1570.