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"Activating mutations in the
epidermal growth factor receptor underlying responsiveness of non-small-cell
lung cancer to gefitinib," by
Thomas J. Lynch and 13 others, New England Journal of Medicine,
350(21): 2129-39, 20 May 2004.
[Authors' affiliations: Massachusetts General
Hospital, Boston, MA; Harvard Medical School, Boston; Harvard
School of Public Health, Boston]
Abstract:
"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."
This 2004 report from the New England
Journal of Medicine was cited 102 times in current journal
articles indexed by Thomson Scientific during September-October 2005. This
latest two-month count maintains the paper's status, for the third consecutive
bimonthly period, as the most-cited paper in medicine published in the last
two years,
aside from reviews. Prior to the most recent bimonthly tally, citations to the
paper have accrued as follows:
July-August 2005: 89 citations
May-June 2005: 96
March-April 2005: 79
January-February 2005: 64
November-December 2004: 41
September-October 2004: 32
July-August 2004: 15
May-June 2004: 3
Total citations to date: 521
SOURCE: Hot
Papers Database (Included with a subscription to the ISI print newsletter Science
Watch®, available from the ISI
Research Services Group. Packaged on a CD-ROM that is mailed with each Science
Watch issue, the Hot
Papers Database contains data on hundreds of highly cited papers published
during the last two years. User interface permits searching by author,
organization, journal, field, and more. Total citations, as well as citations
accrued during successive bimonthly periods, can be assessed and graphed. An
updated CD containing the most recent bimonthly data is mailed with every new
issue of Science
Watch,
six times a year. The CD also includes an electronic version of the Science
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issue in HTML format, for personal desktop access.)
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