On the one hand, contaminating normal cells with wild-type could account for apparent heterozygosity; on the other hand, amplification of mutant hybridization and/or array-based comparative genomic hybridization may help address these issues
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GUID:?9BD10F81-8812-4C11-B75F-8650F38F2D23 pnas_101_36_13306__about.gif (333 bytes) GUID:?25AFA3AD-7454-4414-A748-B0CBA0DCE9B9 pnas_101_36_13306__editorial.gif (517 bytes) GUID:?D87AC021-59DB-4297-9DE4-BF0B5B9273A2 pnas_101_36_13306__contact.gif (369 bytes) GUID:?12C37A72-1356-45F9-98DA-3AE239E374FE pnas_101_36_13306__sitemap.gif (378 bytes) GUID:?19A3F2A5-E0F3-4932-98AE-DE38C0641B87 pnas_101_36_13306__pnashead.gif (1.4K) GUID:?B21F72CB-8898-4132-9E7D-8DD087F8A2CE pnas_101_36_13306__pnasbar.gif (1.9K) GUID:?EC909284-C922-49BB-835E-4394A0CEE5FB pnas_101_36_13306__current_head.gif (501 bytes) GUID:?0B54CE86-D576-4FFD-A1E4-EF8DD7516332 pnas_101_36_13306__spacer.gif (43 bytes) SHCC GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__archives_head.gif (411 bytes) GUID:?AEEEC13E-2652-4230-9217-D0BD0BD299F1 pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__online_head.gif (622 bytes) GUID:?6E9827DB-86CC-4A40-8D06-6B4085E54BCD pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__advsrch_head.gif (481 bytes) GUID:?4E17830F-3F5F-4E7E-8336-D7EAD800DD69 pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__arrowTtrim.gif (51 bytes) GUID:?F9374BAC-E1F2-4854-9FF9-C973DD6AB7EA pnas_101_36_13306__arrowTtrim.gif (51 bytes) GUID:?F9374BAC-E1F2-4854-9FF9-C973DD6AB7EA pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__arrowTtrim.gif (51 bytes) GUID:?F9374BAC-E1F2-4854-9FF9-C973DD6AB7EA pnas_101_36_13306__arrowTtrim.gif (51 bytes) GUID:?F9374BAC-E1F2-4854-9FF9-C973DD6AB7EA Abstract Somatic mutations in the tyrosine kinase (TK) domain name 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 TK domain name that 7 of 10 gefitinib-sensitive tumors experienced comparable types of alterations; no mutations were found in eight gefitinib-refractory tumors (= 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is usually undocumented, experienced analogous somatic mutations, as opposed to none of 10 erlotinib-refractory tumors (= 0.003). Because most mutation-positive tumors were adenocarcinomas from patients who smoked 100 smokes in a lifetime (by no means smokers), we screened exons 2-28 in 15 adenocarcinomas resected from untreated by no means smokers. Seven tumors experienced TK domain name mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (= 0.0001). Immunoblotting of lysates from cells transiently transfected with numerous constructs exhibited 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 that are associated with gefitinib and erlotinib sensitivity. Tyrosine kinases (TKs) regulate signaling pathways that control critical cellular activities (1). When overexpressed or activated by mutations, TKs can contribute to the development of cancers. If tumor cells depend on a mutant TK for survival, as illustrated by certain mouse models of cancer (2, 3), the mutated enzyme can fortuitously serve as an Achilles’ heel for cancer therapy (4). Human examples include BCR-ABL-dependent chronic myelogenous and acute lymphoblastic leukemias (5), are associated with sensitivity of NSCLC to gefitinib (17, 18). In total, deletions or amino acid substitutions in exons 18, 19, and 21 of were found in 13 of 14 tumors sensitive to the drug, but in none of 11 tumors with no response. Lynch and colleagues (17) found mutations in another 2 of 25 primary NSCLCs, and Paez (18) found mutations in 16 of 119 unselected tumors, with a striking predominance of mutations found in 15 of 58 (28%) specimens from Japan as compared to 1 of 61 from the U.S. (2%). To confirm and extend data on gefitinib sensitivity, we examined the status of the TK domain of in tumors that were sensitive.Nine of 12 (75%) mutation-positive tumors in this study had adenocarcinoma histology and were derived from never smokers (Table 1). 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GUID:?9BD10F81-8812-4C11-B75F-8650F38F2D23 pnas_101_36_13306__about.gif COG 133 (333 bytes) GUID:?25AFA3AD-7454-4414-A748-B0CBA0DCE9B9 pnas_101_36_13306__editorial.gif (517 bytes) GUID:?D87AC021-59DB-4297-9DE4-BF0B5B9273A2 pnas_101_36_13306__contact.gif (369 bytes) GUID:?12C37A72-1356-45F9-98DA-3AE239E374FE pnas_101_36_13306__sitemap.gif (378 bytes) GUID:?19A3F2A5-E0F3-4932-98AE-DE38C0641B87 pnas_101_36_13306__pnashead.gif (1.4K) GUID:?B21F72CB-8898-4132-9E7D-8DD087F8A2CE pnas_101_36_13306__pnasbar.gif (1.9K) GUID:?EC909284-C922-49BB-835E-4394A0CEE5FB pnas_101_36_13306__current_head.gif (501 bytes) GUID:?0B54CE86-D576-4FFD-A1E4-EF8DD7516332 pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__archives_head.gif (411 bytes) GUID:?AEEEC13E-2652-4230-9217-D0BD0BD299F1 pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__online_head.gif (622 bytes) GUID:?6E9827DB-86CC-4A40-8D06-6B4085E54BCD pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__advsrch_head.gif (481 bytes) GUID:?4E17830F-3F5F-4E7E-8336-D7EAD800DD69 pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__arrowTtrim.gif (51 bytes) GUID:?F9374BAC-E1F2-4854-9FF9-C973DD6AB7EA pnas_101_36_13306__arrowTtrim.gif (51 bytes) GUID:?F9374BAC-E1F2-4854-9FF9-C973DD6AB7EA pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__arrowTtrim.gif (51 bytes) GUID:?F9374BAC-E1F2-4854-9FF9-C973DD6AB7EA pnas_101_36_13306__arrowTtrim.gif (51 bytes) GUID:?F9374BAC-E1F2-4854-9FF9-C973DD6AB7EA Abstract 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 TK domain that 7 of 10 COG 133 gefitinib-sensitive tumors had similar types of alterations; no mutations were found in eight gefitinib-refractory tumors (= 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 (= 0.003). Because most mutation-positive tumors were adenocarcinomas from patients who smoked 100 cigarettes in a lifetime (never smokers), we screened 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 (= 0.0001). Immunoblotting of lysates from cells transiently transfected with various 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 that are associated with gefitinib and erlotinib sensitivity. Tyrosine kinases (TKs) regulate signaling pathways that control critical cellular activities (1). When overexpressed or activated by mutations, TKs can contribute to the development of cancers. If tumor cells depend on a mutant TK for survival, as illustrated by certain mouse models of cancer (2, 3), the mutated enzyme can fortuitously serve as an Achilles’ heel for cancer therapy (4). Human examples include BCR-ABL-dependent chronic myelogenous and acute lymphoblastic leukemias (5), are associated with sensitivity of NSCLC to gefitinib (17, 18). In total, deletions or amino acid substitutions in exons 18, 19, and 21 of were found in 13 of 14 tumors sensitive to the.Ladanyi from the Memorial Sloan-Kettering Cancer Center for DNA extraction from paraffin-embedded tumors; D. pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__pnasad_etocs.gif (2.0K) GUID:?AA8811AF-5008-47CE-85F8-DFBDBD5C4D26 pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__housenav1.gif (73 bytes) GUID:?DDCBAEDD-90D3-4275-B438-BB55BA8D1176 pnas_101_36_13306__info.gif (511 bytes) GUID:?EE469732-4B01-40C3-84D4-99C24815AD25 pnas_101_36_13306__subscribe.gif (400 bytes) GUID:?9BD10F81-8812-4C11-B75F-8650F38F2D23 pnas_101_36_13306__about.gif (333 bytes) GUID:?25AFA3AD-7454-4414-A748-B0CBA0DCE9B9 pnas_101_36_13306__editorial.gif (517 bytes) GUID:?D87AC021-59DB-4297-9DE4-BF0B5B9273A2 pnas_101_36_13306__contact.gif (369 bytes) GUID:?12C37A72-1356-45F9-98DA-3AE239E374FE pnas_101_36_13306__sitemap.gif (378 bytes) COG 133 GUID:?19A3F2A5-E0F3-4932-98AE-DE38C0641B87 pnas_101_36_13306__pnashead.gif (1.4K) GUID:?B21F72CB-8898-4132-9E7D-8DD087F8A2CE pnas_101_36_13306__pnasbar.gif (1.9K) GUID:?EC909284-C922-49BB-835E-4394A0CEE5FB pnas_101_36_13306__current_head.gif (501 bytes) GUID:?0B54CE86-D576-4FFD-A1E4-EF8DD7516332 pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__archives_head.gif (411 bytes) GUID:?AEEEC13E-2652-4230-9217-D0BD0BD299F1 pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__online_head.gif (622 bytes) GUID:?6E9827DB-86CC-4A40-8D06-6B4085E54BCD pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__advsrch_head.gif (481 bytes) GUID:?4E17830F-3F5F-4E7E-8336-D7EAD800DD69 pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__arrowTtrim.gif (51 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pnas_101_36_13306__editorial.gif (517 bytes) GUID:?D87AC021-59DB-4297-9DE4-BF0B5B9273A2 pnas_101_36_13306__contact.gif (369 bytes) GUID:?12C37A72-1356-45F9-98DA-3AE239E374FE pnas_101_36_13306__sitemap.gif (378 bytes) GUID:?19A3F2A5-E0F3-4932-98AE-DE38C0641B87 pnas_101_36_13306__pnashead.gif (1.4K) GUID:?B21F72CB-8898-4132-9E7D-8DD087F8A2CE pnas_101_36_13306__pnasbar.gif (1.9K) GUID:?EC909284-C922-49BB-835E-4394A0CEE5FB pnas_101_36_13306__current_head.gif (501 bytes) GUID:?0B54CE86-D576-4FFD-A1E4-EF8DD7516332 pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__archives_head.gif (411 bytes) GUID:?AEEEC13E-2652-4230-9217-D0BD0BD299F1 pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__on-line_head.gif (622 bytes) GUID:?6E9827DB-86CC-4A40-8D06-6B4085E54BCD pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__advsrch_head.gif (481 bytes) GUID:?4E17830F-3F5F-4E7E-8336-D7EAD800DD69 pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__arrowTtrim.gif (51 bytes) GUID:?F9374BAC-E1F2-4854-9FF9-C973DD6AB7EA pnas_101_36_13306__arrowTtrim.gif (51 bytes) GUID:?F9374BAC-E1F2-4854-9FF9-C973DD6AB7EA pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__arrowTtrim.gif (51 bytes) GUID:?F9374BAC-E1F2-4854-9FF9-C973DD6AB7EA pnas_101_36_13306__arrowTtrim.gif (51 bytes) GUID:?F9374BAC-E1F2-4854-9FF9-C973DD6AB7EA Abstract Somatic mutations in the tyrosine kinase (TK) website of the epidermal growth element receptor (EGFR) gene are reportedly associated with level of sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions happen in exon 19, whereas point mutations occur regularly in codon 858 (exon 21). We found from sequencing the TK website that 7 of 10 gefitinib-sensitive tumors experienced related types of alterations; no mutations were found in eight gefitinib-refractory tumors (= 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is definitely undocumented, experienced analogous somatic mutations, as opposed to none of 10 erlotinib-refractory tumors (= 0.003). Because most mutation-positive tumors were adenocarcinomas from individuals who smoked 100 smoking cigarettes in a lifetime (by no means smokers), we screened exons 2-28 in 15 adenocarcinomas resected from untreated by no means smokers. Seven tumors experienced TK website mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (= 0.0001). Immunoblotting of lysates from cells transiently transfected with numerous constructs shown 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 display that adenocarcinomas from by no means smokers comprise a distinct subset of lung cancers, frequently comprising mutations within the TK website of that are associated with gefitinib and erlotinib level of sensitivity. Tyrosine kinases (TKs) regulate signaling pathways that control essential cellular activities (1). When overexpressed or triggered by mutations, TKs can contribute to.Genomic DNA was derived from either tumors embedded in paraffin blocks or from new frozen tumors (see and Tables 4 and 5, which are published as encouraging information within the PNAS internet site for PCR primers). bytes) GUID:?9BD10F81-8812-4C11-B75F-8650F38F2D23 pnas_101_36_13306__about.gif (333 bytes) GUID:?25AFA3AD-7454-4414-A748-B0CBA0DCE9B9 pnas_101_36_13306__editorial.gif (517 bytes) GUID:?D87AC021-59DB-4297-9DE4-BF0B5B9273A2 pnas_101_36_13306__contact.gif (369 bytes) GUID:?12C37A72-1356-45F9-98DA-3AE239E374FE pnas_101_36_13306__sitemap.gif (378 bytes) GUID:?19A3F2A5-E0F3-4932-98AE-DE38C0641B87 pnas_101_36_13306__pnashead.gif (1.4K) GUID:?B21F72CB-8898-4132-9E7D-8DD087F8A2CE pnas_101_36_13306__pnasbar.gif (1.9K) GUID:?EC909284-C922-49BB-835E-4394A0CEE5FB pnas_101_36_13306__current_head.gif (501 bytes) GUID:?0B54CE86-D576-4FFD-A1E4-EF8DD7516332 pnas_101_36_13306__spacer.gif (43 bytes) 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GUID:?EC909284-C922-49BB-835E-4394A0CEE5FB pnas_101_36_13306__current_head.gif (501 bytes) GUID:?0B54CE86-D576-4FFD-A1E4-EF8DD7516332 pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__archives_head.gif (411 bytes) GUID:?AEEEC13E-2652-4230-9217-D0BD0BD299F1 pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__on-line_head.gif (622 bytes) GUID:?6E9827DB-86CC-4A40-8D06-6B4085E54BCD pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__advsrch_head.gif (481 bytes) GUID:?4E17830F-3F5F-4E7E-8336-D7EAD800DD69 pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__arrowTtrim.gif (51 bytes) GUID:?F9374BAC-E1F2-4854-9FF9-C973DD6AB7EA pnas_101_36_13306__arrowTtrim.gif (51 bytes) GUID:?F9374BAC-E1F2-4854-9FF9-C973DD6AB7EA pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__arrowTtrim.gif (51 bytes) GUID:?F9374BAC-E1F2-4854-9FF9-C973DD6AB7EA pnas_101_36_13306__arrowTtrim.gif (51 bytes) GUID:?F9374BAC-E1F2-4854-9FF9-C973DD6AB7EA Abstract Somatic mutations in the tyrosine kinase (TK) website of the epidermal growth element receptor (EGFR) gene are reportedly associated with level of sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions happen in exon 19, whereas point mutations occur regularly in codon 858 (exon 21). We found from sequencing the TK website that 7 of 10 gefitinib-sensitive tumors experienced related COG 133 types of alterations; no mutations were found in eight gefitinib-refractory tumors (= 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is definitely undocumented, experienced analogous somatic mutations, as opposed to none of 10 erlotinib-refractory tumors (= 0.003). Because most mutation-positive tumors were adenocarcinomas from individuals who smoked 100 smoking cigarettes in a lifetime (by no means smokers), we screened exons 2-28 in 15 adenocarcinomas resected from untreated by no means smokers. Seven tumors experienced TK website mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (= 0.0001). Immunoblotting of lysates from cells transiently transfected with numerous constructs shown 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 by no means smokers comprise a distinct subset of lung cancers, frequently made up of mutations within the TK domain name of that are associated with gefitinib and erlotinib sensitivity. Tyrosine kinases (TKs) regulate signaling pathways that control crucial cellular activities (1). When overexpressed or activated by mutations, TKs can contribute to the development of cancers. If tumor cells depend on a mutant TK for survival, as illustrated by certain mouse models of malignancy (2, 3), the mutated enzyme can fortuitously serve as an Achilles’ heel for malignancy therapy (4). Human examples include BCR-ABL-dependent chronic myelogenous and acute lymphoblastic leukemias (5), are associated with sensitivity of NSCLC to gefitinib (17, 18). In total, deletions or amino acid substitutions in exons 18, 19, and.For drug-sensitive tumors that did not have mutations, sequences from exons 19 and 21 were also determined from at least two independently derived PCR products. 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GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__online_head.gif (622 COG 133 bytes) GUID:?6E9827DB-86CC-4A40-8D06-6B4085E54BCD pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__advsrch_head.gif (481 bytes) GUID:?4E17830F-3F5F-4E7E-8336-D7EAD800DD69 pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__arrowTtrim.gif (51 bytes) GUID:?F9374BAC-E1F2-4854-9FF9-C973DD6AB7EA pnas_101_36_13306__arrowTtrim.gif (51 bytes) GUID:?F9374BAC-E1F2-4854-9FF9-C973DD6AB7EA pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__spacer.gif (43 bytes) GUID:?E59F8C5E-F4AB-43F3-BE0D-5A148F855E22 pnas_101_36_13306__arrowTtrim.gif (51 bytes) GUID:?F9374BAC-E1F2-4854-9FF9-C973DD6AB7EA pnas_101_36_13306__arrowTtrim.gif (51 bytes) GUID:?F9374BAC-E1F2-4854-9FF9-C973DD6AB7EA Abstract Somatic mutations in the tyrosine kinase (TK) domain name 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 TK domain name that 7 of 10 gefitinib-sensitive tumors experienced comparable types of alterations; no mutations were found in eight gefitinib-refractory tumors (= 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is usually undocumented, experienced analogous somatic mutations, as opposed to none of 10 erlotinib-refractory tumors (= 0.003). Because most mutation-positive tumors were adenocarcinomas from patients who smoked 100 smokes in a lifetime (by no means smokers), we screened exons 2-28 in 15 adenocarcinomas resected from untreated by no means smokers. Seven tumors experienced TK domain name mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (= 0.0001). Immunoblotting of lysates from cells transiently transfected with numerous constructs exhibited 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 by no means smokers comprise a distinct subset of lung cancers, frequently made up of mutations within the TK domain name of that are associated with gefitinib and erlotinib sensitivity. Tyrosine kinases (TKs) regulate signaling pathways that control crucial cellular activities (1). When overexpressed or activated by mutations, TKs can contribute to the introduction of malignancies. If tumor cells rely on the mutant TK for success, as illustrated by specific mouse types of cancers (2, 3), the mutated enzyme can fortuitously serve as an Achilles’ high heel for tumor therapy.