EGFR genetic heterogeneity of nonsmall cell lung cancers contributing to acquired gefitinib resistance.

EGFR genetic heterogeneity of nonsmall cell lung cancers contributing to acquired gefitinib resistance. Research Abstract Details 

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EGFR genetic heterogeneity of nonsmall cell lung cancers contributing to acquired gefitinib resistance. Abstract Text:

Gefitinib is dramatically effective for nonsmall cell lung cancers (NSCLCs) with activating mutations of the epidermal growth factor receptor (EGFR) gene, but these tumors eventually develop drug resistance, attributable to a secondary T790M mutation or acquired MET amplification in some relapsed tumors. We analyzed EGFR mutations in matched pre- and post-therapeutic tumors of 6 gefitinib-responding lung cancers. With conventional PCR-based sequencing, classic mutations were detected in pretreatment samples of each case. The same mutations were readily confirmed in treated lesions of 4 cases, but were absent in those of Cases 1 and 2. Subsequent mutant-enriched peptide-nucleic-acid-mediated PCR clamping and subcloning assays detected the mutation in minor cells of treated lesions of Case 1, but still failed to detect a mutation in Case 2. We thus performed microdissection-based cell cluster mutation analysis of pretreatment tumors, and found that 3, including the first 2, concurrently contained tumor cells with either mutant or wild-type EGFR, although the latter was only a minor fraction. These findings suggest that some NSCLCs are genetically heterogeneous with regard to EGFR mutations; gefitinib-sensitive mutants decrease or vanish while wild clones selectively survive with gefitinib treatment. In addition, T790M was detected in a small fraction of treated lesions of 3 cases, and MET amplification was revealed in 3 treated tumors of Case 2. Thus, our results suggest that multiple mechanisms underlie acquired gefitinib resistance, and selection on a background of EGFR genetic heterogeneity also contributes to acquisition of resistance in a proportion of NSCLCs.

EGFR genetic heterogeneity of nonsmall cell lung cancers contributing to acquired gefitinib resistance. Publishing Authors By Initials

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EGFR genetic heterogeneity of nonsmall cell lung cancers contributing to acquired gefitinib resistance. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: International journal of cancer. Journal internati

VOLUME: 123

Page Numbers: 2480-6

Journal Abbreviation: Int. J. Cancer

ISSN: 1097-0215

DAY: 1

MONTH: Dec

YEAR: 2008

EGFR genetic heterogeneity of nonsmall cell lung cancers contributing to acquired gefitinib resistance. Information

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LANGUAGE: eng

NlmUniqueID: 42124

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Grant and Affiliation Information for EGFR genetic heterogeneity of nonsmall cell lung cancers contributing to acquired gefitinib resistance.

AFFILIATION: Department of Pathology, Kitasato University School of Medicine, Kanagawa, Japan. sxjiang@med.kitasato-u.ac.jp

Country: United States

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MEDLINETA: Int J Cancer

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