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Journal List > PLoS Med > v.2(1); Jan 2005

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PLoS Med. 2005 January; 2(1): e17.
Published online 2005 January 25. doi: 10.1371/journal.pmed.0020017.
PMCID: PMC545207
Copyright : © 2005 Pao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
KRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib
William Pao,1,2* Theresa Y Wang,1 Gregory J Riely,2 Vincent A Miller,2 Qiulu Pan,3 Marc Ladanyi,3 Maureen F Zakowski,3 Robert T Heelan,4 Mark G Kris,2 and Harold E Varmus1
1Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
2Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
3Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
4Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
Roy Herbst, Academic Editor
MD Anderson Cancer Center, United States of America
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.
*To whom correspondence should be addressed. E-mail: paow/at/mskcc.org
Received October 14, 2004; Accepted November 28, 2004.
Small right arrow pointing to: See "Predicting Tumor Responses to Gefitinib and Erlotinib" , e21.
Small right arrow pointing to: See "Three More Learning Points" , e30.
 
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Abstract
Background
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.
Methods and Findings
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.
Conclusion
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.
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