BACKGROUND: Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown. METHODS: We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells. RESULTS: Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. CONCLUSIONS: A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib. Copyright 2004 Massachusetts Medical Society
BACKGROUND: Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown. METHODS: We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells. RESULTS: Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. CONCLUSIONS: A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib. Copyright 2004 Massachusetts Medical Society
Authors: Youngmi Kim; Eunhee Kim; Qiulian Wu; Olga Guryanova; Masahiro Hitomi; Justin D Lathia; David Serwanski; Andrew E Sloan; Robert J Weil; Jeongwu Lee; Akiko Nishiyama; Shideng Bao; Anita B Hjelmeland; Jeremy N Rich Journal: Genes Dev Date: 2012-06-01 Impact factor: 11.361
Authors: M Ponz-Sarvisé; J Rodríguez; A Viudez; A Chopitea; A Calvo; J García-Foncillas; I Gil-Bazo Journal: World J Gastroenterol Date: 2007-11-28 Impact factor: 5.742
Authors: Youngwook Kim; Peter S Hammerman; Jaegil Kim; Ji-ae Yoon; Yoomi Lee; Jong-Mu Sun; Matthew D Wilkerson; Chandra Sekhar Pedamallu; Kristian Cibulskis; Yeong Kyung Yoo; Michael S Lawrence; Petar Stojanov; Scott L Carter; Aaron McKenna; Chip Stewart; Andrey Y Sivachenko; In-Jae Oh; Hong Kwan Kim; Yong Soo Choi; Kwhanmien Kim; Young Mog Shim; Kyu-Sik Kim; Sang-Yun Song; Kook-Joo Na; Yoon-La Choi; D Neil Hayes; Jhingook Kim; Sukki Cho; Young-Chul Kim; Jin Seok Ahn; Myung-Ju Ahn; Gad Getz; Matthew Meyerson; Keunchil Park Journal: J Clin Oncol Date: 2013-12-09 Impact factor: 44.544
Authors: Martin L Sos; Felix Dietlein; Martin Peifer; Jakob Schöttle; Hyatt Balke-Want; Christian Müller; Mirjam Koker; André Richters; Stefanie Heynck; Florian Malchers; Johannes M Heuckmann; Danila Seidel; Patrick A Eyers; Roland T Ullrich; Andrey P Antonchick; Viktor V Vintonyak; Peter M Schneider; Takashi Ninomiya; Herbert Waldmann; Reinhard Büttner; Daniel Rauh; Lukas C Heukamp; Roman K Thomas Journal: Proc Natl Acad Sci U S A Date: 2012-10-03 Impact factor: 11.205