KRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib

Somatic mutations in the gene for the epidermal growth factor receptor (EGFR) are found in adenocarcinomas of the lung and are associated with sensitivity to the kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Lung adenocarcinomas also harbor activating mutations in the downstream GTPa...

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Published in	PLoS medicine Vol. 2; no. 1; p. e17
Main Authors	Pao, William, Wang, Theresa Y, Riely, Gregory J, Miller, Vincent A, Pan, Qiulu, Ladanyi, Marc, Zakowski, Maureen F, Heelan, Robert T, Kris, Mark G, Varmus, Harold E
Format	Journal Article
Language	English
Published	United States Public Library of Science 01.01.2005 Public Library of Science (PLoS)
Subjects	Adenocarcinoma - drug therapy Adenocarcinoma - genetics Antineoplastic Agents - pharmacology Cancer: Lung Capillary electrophoresis Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - genetics Clinical trials Decision Making Drug Resistance, Neoplasm Epidermal growth factor Erlotinib Hydrochloride Genes, ras Genetics Genetics/Genomics/Gene Therapy Humans Kinases Lung cancer Lung Neoplasms - drug therapy Lung Neoplasms - genetics Medical research Mutation Oncology Patients Quinazolines - pharmacology Research funding Treatment Outcome Tumors United States > US Adenocarcinoma Decision Making Carcinoma, Non-Small-Cell Lung Humans Antineoplastic Agents Drug Resistance, Neoplasm Treatment Outcome Quinazolines Genes, ras Lung Neoplasms
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ISSN	1549-1676 1549-1277 1549-1676
DOI	10.1371/journal.pmed.0020017

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Summary:	Somatic mutations in the gene for the epidermal growth factor receptor (EGFR) are found in adenocarcinomas of the lung and are associated with sensitivity to the kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Lung adenocarcinomas also harbor activating mutations in the downstream GTPase, KRAS, and mutations in EGFR and KRAS appear to be mutually exclusive. We sought to determine whether mutations in KRAS could be used to further enhance prediction of response to gefitinib or erlotinib. We screened 60 lung adenocarcinomas defined as sensitive or refractory to gefitinib or erlotinib for mutations in EGFR and KRAS. We show that mutations in KRAS are associated with a lack of sensitivity to either drug. Our results suggest that treatment decisions regarding use of these kinase inhibitors might be improved by determining the mutational status of both EGFR and KRAS.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Competing Interests: VAM has received research funding from Genentech (co-developer of erlotinib). He has received honoraria from AstraZeneca (maker of gefitinib) for consultancy. MGK has received research funding from AstraZeneca and research funding and consulting fees from Genentech and has represented AstraZeneca before the US Food and Drug Administration. WP, VAM, MFZ, and HEV, represented by the Sloan-Kettering Institute for Cancer Research, filed on June 1, 2004, a provisional patent application entitled “Use of mutations in EGFR kinase as an indicator of therapeutic efficacy of erlotinib in the treatment of NSCLC,” serial number 60/576,275. HEV is Co-founder and Chair of the Board of Directors of the Public Library of Science. Author Contributions: WP and HEV designed the study. QP and ML designed and performed more sensitive methods to detect EGFR mutations. WP, TYW, GJR, VAM, MFZ, MGK, and RTH acquired and analyzed the data. WP, TYW, and HEV contributed to writing the paper.
ISSN:	1549-1676 1549-1277 1549-1676
DOI:	10.1371/journal.pmed.0020017