PMID- 15118073
OWN - NLM
STAT- MEDLINE
DCOM- 20040525
LR  - 20240103
IS  - 1533-4406 (Electronic)
IS  - 0028-4793 (Linking)
VI  - 350
IP  - 21
DP  - 2004 May 20
TI  - Activating mutations in the epidermal growth factor receptor underlying 
      responsiveness of non-small-cell lung cancer to gefitinib.
PG  - 2129-39
AB  - BACKGROUND: Most patients with non-small-cell lung cancer have no response to the 
      tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor 
      receptor (EGFR). However, about 10 percent of patients have a rapid and often 
      dramatic clinical response. The molecular mechanisms underlying sensitivity to 
      gefitinib are unknown. METHODS: We searched for mutations in the EGFR gene in 
      primary tumors from patients with non-small-cell lung cancer who had a response 
      to gefitinib, those who did not have a response, and those who had not been 
      exposed to gefitinib. The functional consequences of identified mutations were 
      evaluated after the mutant proteins were expressed in cultured cells. RESULTS: 
      Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene 
      in eight of nine patients with gefitinib-responsive lung cancer, as compared with 
      none of the seven patients with no response (P<0.001). Mutations were either 
      small, in-frame deletions or amino acid substitutions clustered around the 
      ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected 
      in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had 
      not been exposed to gefitinib (8 percent). All mutations were heterozygous, and 
      identical mutations were observed in multiple patients, suggesting an additive 
      specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine 
      kinase activity in response to epidermal growth factor and increased sensitivity 
      to inhibition by gefitinib. CONCLUSIONS: A subgroup of patients with 
      non-small-cell lung cancer have specific mutations in the EGFR gene, which 
      correlate with clinical responsiveness to the tyrosine kinase inhibitor 
      gefitinib. These mutations lead to increased growth factor signaling and confer 
      susceptibility to the inhibitor. Screening for such mutations in lung cancers may 
      identify patients who will have a response to gefitinib.
CI  - Copyright 2004 Massachusetts Medical Society
FAU - Lynch, Thomas J
AU  - Lynch TJ
AD  - Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston 
      02129, USA.
FAU - Bell, Daphne W
AU  - Bell DW
FAU - Sordella, Raffaella
AU  - Sordella R
FAU - Gurubhagavatula, Sarada
AU  - Gurubhagavatula S
FAU - Okimoto, Ross A
AU  - Okimoto RA
FAU - Brannigan, Brian W
AU  - Brannigan BW
FAU - Harris, Patricia L
AU  - Harris PL
FAU - Haserlat, Sara M
AU  - Haserlat SM
FAU - Supko, Jeffrey G
AU  - Supko JG
FAU - Haluska, Frank G
AU  - Haluska FG
FAU - Louis, David N
AU  - Louis DN
FAU - Christiani, David C
AU  - Christiani DC
FAU - Settleman, Jeff
AU  - Settleman J
FAU - Haber, Daniel A
AU  - Haber DA
LA  - eng
GR  - P01 95281/PHS HHS/United States
GR  - P30 CA0516/CA/NCI NIH HHS/United States
GR  - P50 CA 090578/CA/NCI NIH HHS/United States
GR  - R01 CA 092824/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20040429
PL  - United States
TA  - N Engl J Med
JT  - The New England journal of medicine
JID - 0255562
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Quinazolines)
RN  - 62229-50-9 (Epidermal Growth Factor)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - S65743JHBS (Gefitinib)
SB  - IM
CIN - N Engl J Med. 2004 May 20;350(21):2191-3. PMID: 15118072
CIN - N Engl J Med. 2004 Sep 16;351(12):1260-1; author reply 1260-1. PMID: 15371587
CIN - N Engl J Med. 2004 Sep 16;351(12):1260-1; author reply 1260-1. PMID: 15376351
CIN - N Engl J Med. 2004 Sep 16;351(12):1260-1; author reply 1260-1. PMID: 15376352
CIN - Adv Anat Pathol. 2005 Mar;12(2):47-52. PMID: 15731572
CIN - N Engl J Med. 2005 Jul 14;353(2):209-10. PMID: 16014895
MH  - Adenocarcinoma/drug therapy/genetics
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Amino Acid Sequence
MH  - Antineoplastic Agents/*therapeutic use
MH  - Base Sequence
MH  - Carcinoma, Non-Small-Cell Lung/drug therapy/*genetics
MH  - DNA Mutational Analysis
MH  - Drug Resistance, Neoplasm/genetics
MH  - Epidermal Growth Factor/metabolism
MH  - ErbB Receptors/chemistry/*genetics/metabolism
MH  - Female
MH  - Gefitinib
MH  - *Genes, erbB-1
MH  - Heterozygote
MH  - Humans
MH  - Lung Neoplasms/drug therapy/*genetics
MH  - Male
MH  - Middle Aged
MH  - Molecular Sequence Data
MH  - Mutation
MH  - Protein-Tyrosine Kinases/*antagonists & inhibitors/genetics/metabolism
MH  - Quinazolines/*therapeutic use
MH  - *Sequence Deletion
EDAT- 2004/05/01 05:00
MHDA- 2004/05/27 05:00
CRDT- 2004/05/01 05:00
PHST- 2004/05/01 05:00 [pubmed]
PHST- 2004/05/27 05:00 [medline]
PHST- 2004/05/01 05:00 [entrez]
AID - NEJMoa040938 [pii]
AID - 10.1056/NEJMoa040938 [doi]
PST - ppublish
SO  - N Engl J Med. 2004 May 20;350(21):2129-39. doi: 10.1056/NEJMoa040938. Epub 2004 
      Apr 29.