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

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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.

          Abstract

          Mutational analysis of the KRAS gene in lung cancer patients treated with two different kinase inhibitors suggests that tumors with KRAS mutations do not respond to these drugs

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          Most cited references11

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          EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.

          Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). We found from sequencing the EGFR TK domain that 7 of 10 gefitinib-sensitive tumors had similar types of alterations; no mutations were found in eight gefitinib-refractory tumors (P = 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is undocumented, had analogous somatic mutations, as opposed to none of 10 erlotinib-refractory tumors (P = 0.003). Because most mutation-positive tumors were adenocarcinomas from patients who smoked <100 cigarettes in a lifetime ("never smokers"), we screened EGFR exons 2-28 in 15 adenocarcinomas resected from untreated never smokers. Seven tumors had TK domain mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (P = 0.0001). Immunoblotting of lysates from cells transiently transfected with various EGFR constructs demonstrated that, compared to wild-type protein, an exon 19 deletion mutant induced diminished levels of phosphotyrosine, whereas the phosphorylation at tyrosine 1092 of an exon 21 point mutant was inhibited at 10-fold lower concentrations of drug. Collectively, these data show that adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity.
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            Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung.

            The majority of lung carcinoma cases occur in current or former smokers. K-ras gene mutations are common in lung adenocarcinoma and have been associated with cigarette smoking, asbestos exposure, and female gender. In the current study, the authors examined the contribution of cigarette smoking to K-ras gene mutations in patients with primary lung adenocarcinoma. Smoking histories were obtained from 106 prospectively enrolled patients with primary adenocarcinoma of the lung. K-ras mutations were detected in the primary tumor using an allele-specific ligation assay. Ninety-two of the 106 patients (87%) with lung adenocarcinoma were smokers. Nonsmokers with this tumor were more likely to be women (11 of 14; 79%), whereas the majority of smokers (57%) were men. K-ras mutations were detected in 40 of 106 tumors (38%) and were significantly more common in smokers compared with nonsmokers (43% vs. 0%; P = 0.001). The results of the current study confirm and extend previous observations that smokers with adenocarcinoma of the lung are more likely to have K-ras mutant tumors compared with nonsmokers. The strong link between cigarette smoking and K-ras mutations in adenocarcinoma of the lung supports the role of specific tobacco carcinogens in the etiology of this malignancy. Copyright 2001 American Cancer Society.
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              Mutations and addiction to EGFR: the Achilles 'heal' of lung cancers?

              The epidermal growth factor receptor (EGFR) gene product is a receptor tyrosine kinase (TK) that affects many important downstream pathways. The recent finding that mutations in EGFR predict the response of lung cancers to therapies that target the TK domain of the gene product has generated considerable interest. The mutations are associated with adenocarcinoma histology, oriental origin, female gender and never-smoker status. Most mutations target structures in the TK domain that appear to be essential for the phosphorylation function of the gene. Cancer cells with mutant EGFR genes might become physiologically dependent on the continued activity of the gene for the maintenance of their malignant phenotype; however, this might also be a target for therapy.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Med
                pmed
                PLoS Medicine
                Public Library of Science (San Francisco, USA )
                1549-1277
                1549-1676
                January 2005
                25 January 2005
                : 2
                : 1
                : e17
                Affiliations
                [1] 1Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center New York, New YorkUnited States of America
                [2] 2Department of Medicine, Memorial Sloan-Kettering Cancer Center New York, New YorkUnited States of America
                [3] 3Department of Pathology, Memorial Sloan-Kettering Cancer Center New York, New YorkUnited States of America
                [4] 4Department of Radiology, Memorial Sloan-Kettering Cancer Center New York, New YorkUnited States of America
                MD Anderson Cancer Center United States of America
                Author notes

                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@ 123456mskcc.org
                Article
                10.1371/journal.pmed.0020017
                545207
                15696205
                ee7a59d4-cb71-47fd-9eb7-d16de59143e5
                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
                History
                : 14 October 2004
                : 28 November 2004
                Categories
                Research Article
                Genetics/Genomics/Gene Therapy
                Oncology
                Oncology
                Cancer: Lung
                Genetics

                Medicine
                Medicine

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