Journal ArticleDOI
EGFR Mutation and Resistance of Non–Small-Cell Lung Cancer to Gefitinib
Susumu Kobayashi,Titus J. Boggon,Tajhal Dayaram,Pasi A. Jänne,Olivier Kocher,Matthew Meyerson,Bruce E. Johnson,Michael J. Eck,Daniel G. Tenen,Balazs Halmos,Balazs Halmos +10 more
TLDR
In this paper, the authors reported the case of a patient with EGFR-mutant, gefitinib-responsive, advanced non-small-cell lung cancer who had a relapse after two years of complete remission.Abstract:
Mutations of the epidermal growth factor receptor (EGFR) gene have been identified in specimens from patients with non-small-cell lung cancer who have a response to anilinoquinazoline EGFR inhibitors. Despite the dramatic responses to such inhibitors, most patients ultimately have a relapse. The mechanism of the drug resistance is unknown. Here we report the case of a patient with EGFR-mutant, gefitinib-responsive, advanced non-small-cell lung cancer who had a relapse after two years of complete remission during treatment with gefitinib. The DNA sequence of the EGFR gene in his tumor biopsy specimen at relapse revealed the presence of a second point mutation, resulting in threonine-to-methionine amino acid change at position 790 of EGFR. Structural modeling and biochemical studies showed that this second mutation led to gefitinib resistance.read more
Citations
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Cancer drug resistance: an evolving paradigm
TL;DR: There are now unprecedented opportunities to understand and overcome drug resistance through the clinical assessment of rational therapeutic drug combinations and the use of predictive biomarkers to enable patient stratification.
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Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors
Lecia V. Sequist,Belinda A. Waltman,Dora Dias-Santagata,Subba R. Digumarthy,Alexa B. Turke,Panos Fidias,Kristin Bergethon,Alice T. Shaw,Scott N. Gettinger,Arjola K. Cosper,Sara Akhavanfard,Rebecca S. Heist,Jennifer S. Temel,James G. Christensen,John C. Wain,Thomas J. Lynch,Kathy Vernovsky,Eugene J. Mark,Michael Lanuti,A. John Iafrate,Mari Mino-Kenudson,Jeffrey A. Engelman +21 more
TL;DR: Detailed genetic and histological analysis of 37 patients with drug-resistant non–small cell lung cancers carrying EGFR mutations provides new insights into the shifting sands of drug resistance evolution in lung cancers and suggests that serial biopsies may be essential in the quest to reverse or even prevent the development ofdrug resistance.
Journal ArticleDOI
The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism
TL;DR: In light of the recent advances in understanding of the function of PI3Ks in the pathogenesis of diabetes and cancer, the exciting therapeutic opportunities for targeting this pathway to treat these diseases are discussed.
Journal ArticleDOI
Epidermal growth factor receptor mutations in lung cancer
TL;DR: 'oncogenic shock' is described as a mechanistic explanation for the apoptosis that follows the acute treatment of susceptible cells with kinase inhibitors, essential to the successful use of targeted therapies in common epithelial cancers.
Journal ArticleDOI
Somatic mutations affect key pathways in lung adenocarcinoma
Li Ding,Gad Getz,David A. Wheeler,Elaine R. Mardis,Michael D. McLellan,Kristian Cibulskis,Carrie Sougnez,Heidi Greulich,Heidi Greulich,Donna M. Muzny,Margaret Morgan,Lucinda Fulton,Robert S. Fulton,Qunyuan Zhang,Michael C. Wendl,Michael S. Lawrence,David E. Larson,Ken Chen,David J. Dooling,Aniko Sabo,Alicia Hawes,Hua Shen,Shalini N. Jhangiani,Lora Lewis,Otis Hall,Yiming Zhu,Tittu Mathew,Yanru Ren,Jiqiang Yao,Steven E. Scherer,Kerstin Clerc,Ginger A. Metcalf,Brian Ng,Aleksandar Milosavljevic,Manuel L. Gonzalez-Garay,John R. Osborne,Rick Meyer,Xiaoqi Shi,Yuzhu Tang,Daniel C. Koboldt,Ling Lin,Rachel Abbott,Tracie L. Miner,Craig Pohl,Ginger A. Fewell,Carrie A. Haipek,Heather Schmidt,Brian H. Dunford-Shore,Aldi T. Kraja,Seth D. Crosby,Christopher S. Sawyer,Tammi L. Vickery,Sacha N. Sander,Jody S. Robinson,Wendy Winckler,Wendy Winckler,Jennifer Baldwin,Lucian R. Chirieac,Amit Dutt,Amit Dutt,Timothy Fennell,Megan Hanna,Megan Hanna,Bruce E. Johnson,Robert C. Onofrio,Roman K. Thomas,Giovanni Tonon,Barbara A. Weir,Barbara A. Weir,Xiaojun Zhao,Xiaojun Zhao,Liuda Ziaugra,Michael C. Zody,Thomas J. Giordano,Mark B. Orringer,Jack A. Roth,Margaret R. Spitz,Ignacio I. Wistuba,Bradley A. Ozenberger,Peter J. Good,Andrew C. Chang,David G. Beer,Mark A. Watson,Marc Ladanyi,Stephen R. Broderick,Akihiko Yoshizawa,William D. Travis,William Pao,Michael A. Province,George M. Weinstock,Harold E. Varmus,Stacey Gabriel,Eric S. Lander,Richard A. Gibbs,Matthew Meyerson,Matthew Meyerson,Richard K. Wilson +96 more
TL;DR: Somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B are found.
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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