EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib
William Pao,Vincent A. Miller,Maureen F. Zakowski,Jennifer Doherty,Katerina Politi,Inderpal S. Sarkaria,Bhuvanesh Singh,Robert T. Heelan,Valerie W. Rusch,Lucinda Fulton,Elaine R. Mardis,Doris M. Kupfer,Richard K. Wilson,Mark G. Kris,Harold E. Varmus +14 more
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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.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 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.read more
Citations
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Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma
Tony Mok,Yi-Long Wu,Sumitra Thongprasert,Chih-Hsin Yang,Da Tong Chu,Nagahiro Saijo,Patrapim Sunpaweravong,Baohui Han,Benjamin Margono,Benjamin Margono,Yukito Ichinose,Yutaka Nishiwaki,Yuichiro Ohe,Jin Ji Yang,Busyamas Chewaskulyong,Haiyi Jiang,Emma Duffield,Claire Watkins,Alison Armour,Masahiro Fukuoka +19 more
TL;DR: Gefit inib is superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia and the presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib.
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Erlotinib in previously treated non-small-cell lung cancer.
Frances A. Shepherd,José Rodrigues Pereira,Tudor Ciuleanu,Eng Huat Tan,Vera Hirsh,Sumitra Thongprasert,Daniel Campos,Savitree Maoleekoonpiroj,Michael Smylie,Renato G. Martins,Maximiliano Van Kooten,Mircea Dediu,B. Findlay,Dongsheng Tu,Dianne Johnston,Andrea Bezjak,Gary M. Clark,Pedro Santabárbara,Lesley Seymour +18 more
TL;DR: Elotinib can prolong survival in patients with non-small-cell lung cancer after first-line or second-line chemotherapy, and five percent of patients discontinued erlot inib because of toxic effects.
Journal ArticleDOI
Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer
Manabu Soda,Young Lim Choi,Munehiro Enomoto,Shuji Takada,Yoshihiro Yamashita,Shunpei Ishikawa,Shin-ichiro Fujiwara,Hideki Watanabe,Kentaro Kurashina,Hisashi Hatanaka,Masashi Bando,Shoji Ohno,Yuichi Ishikawa,Hiroyuki Aburatani,Toshiro Niki,Yasunori Sohara,Yukihiko Sugiyama,Hiroyuki Mano +17 more
TL;DR: It is shown that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells.
Journal ArticleDOI
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.
Rafael Rosell,Enric Carcereny,Radj Gervais,A. Vergnenegre,Bartomeu Massuti,Enriqueta Felip,Ramon Palmero,Ramon Garcia-Gomez,Cinta Pallares,Jose Miguel Sanchez,Rut Porta,Manuel Cobo,Pilar Garrido,Flavia Longo,Teresa Moran,A. Insa,Filippo de Marinis,Romain Corre,Isabel Bover,Alfonso Illiano,Eric Dansin,Javier de Castro,Michele Milella,Noemi Reguart,Giuseppe Altavilla,Ulpiano Jimenez,Mariano Provencio,Miguel Angel Moreno,J. Terrasa,Jose Muñoz-Langa,Javier Valdivia,Dolores Isla,Manuel Domine,Olivier Molinier,Julien Mazieres,Nathalie Baize,Rosario García-Campelo,Gilles Robinet,Delvys Rodriguez-Abreu,Guillermo Lopez-Vivanco,Vittorio Gebbia,Lioba Ferrera-Delgado,Pierre Bombaron,R. Bernabé,Alessandra Bearz,Angel Artal,Enrico Cortesi,Christian Rolfo,Maria Sanchez-Ronco,Ana Drozdowskyj,Cristina Queralt,Itziar de Aguirre,Jose Luis Ramirez,Jose Javier Sanchez,Miguel Angel Molina,Miquel Taron,Luis Paz-Ares +56 more
TL;DR: Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations as discussed by the authors.
Journal ArticleDOI
Anaplastic Lymphoma Kinase Inhibition in Non–Small-Cell Lung Cancer
Eunice L. Kwak,Yung-Jue Bang,D. Ross Camidge,Alice T. Shaw,Benjamin Solomon,Robert G. Maki,Sai-Hong Ignatius Ou,Bruce J. Dezube,Pasi A. Jänne,Daniel B. Costa,Marileila Varella-Garcia,Woo-Ho Kim,Thomas J. Lynch,Panos Fidias,Hannah Stubbs,Jeffrey A. Engelman,Lecia V. Sequist,Weiwei Tan,Leena Gandhi,Mari Mino-Kenudson,Greg C. Wei,S. Martin Shreeve,Mark J. Ratain,Jeffrey Settleman,James G. Christensen,Daniel A. Haber,Keith D. Wilner,Ravi Salgia,Geoffrey I. Shapiro,Jeffrey W. Clark,A. John Iafrate +30 more
TL;DR: The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients, and the drug resulted in grade 1 or 2 gastrointestinal side effects.
References
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Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib
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Journal ArticleDOI
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Journal ArticleDOI
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Journal ArticleDOI
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TL;DR: It is found that drug resistance is associated with the reactivation of BCR-ABL signal transduction in all cases examined and a strategy for identifying inhibitors of STI-571 resistance is suggested.
Journal ArticleDOI
Multi-Institutional Randomized Phase II Trial of Gefitinib for Previously Treated Patients With Advanced Non–Small-Cell Lung Cancer
Masahiro Fukuoka,Seiji Yano,Giuseppe Giaccone,Tomohide Tamura,Kazuhiko Nakagawa,Jean-Yves Douillard,Yutaka Nishiwaki,Johan Vansteenkiste,Shinzoh Kudoh,Danny Rischin,Richard Eek,Takeshi Horai,Kazumasa Noda,Ichiro Takata,Egbert F. Smit,Steven D. Averbuch,Angela Macleod,A. Feyereislova,Rui Ping Dong,José Baselga +19 more
TL;DR: Gefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in patients with pretreated advanced non-small-cell lung cancer.
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