Journal ArticleDOI
Molecular Correlates of Imatinib Resistance in Gastrointestinal Stromal Tumors
Michael Heinrich,Christopher L. Corless,Charles D. Blanke,George D. Demetri,Heikki Joensuu,Peter J. Roberts,Burton L. Eisenberg,Margaret von Mehren,Christopher D.M. Fletcher,Katrin Sandau,Karen McDougall,Wen-Bin Ou,Chang Jie Chen,Jonathan A. Fletcher +13 more
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TLDR
Using RNAi technology, it is demonstrated that imatinib-resistant GIST cells remain dependent on KIT kinase activity for activation of critical downstream signaling pathways, which has implications for future approaches to the growing problem ofImatinib resistance in patients with advanced GISTs.Abstract:
Purpose Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT or platelet-derived growth factor alpha (PDGFRA) kinases, which are targets for imatinib. In clinical studies, 75% to 90% of patients with advanced GISTs experience clinical benefit from imatinib. However, imatinib resistance is an increasing clinical problem. Patients and Methods One hundred forty-seven patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib. Specimens from pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. Secondary kinase mutations of KIT or PDGFRA that were identified in imatinib-resistant GISTs were biochemically profiled for imatinib sensitivity. Results Molecular studies were performed using specimens from 10 patients with primary and 33 patients with secondary resistance. Imatinib-resistant tumors had levels of activated KIT that were similar to or greater than those ...read more
Citations
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Journal ArticleDOI
MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling
Jeffrey A. Engelman,Kreshnik Zejnullahu,Tetsuya Mitsudomi,Youngchul Song,Courtney Hyland,Joon Oh Park,Neal I. Lindeman,Christopher-Michael Gale,Xiaojun Zhao,James J. Christensen,Takayuki Kosaka,Alison J. Holmes,Andrew M. Rogers,Federico Cappuzzo,Tony Mok,Charles Lee,Bruce E. Johnson,Lewis C. Cantley,Pasi A. Jänne +18 more
TL;DR: It is proposed that MET amplification may promote drug resistance in other ERBB-driven cancers as well after it was found that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)–dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors.
Journal ArticleDOI
COT drives resistance to RAF inhibition through MAP kinase pathway reactivation
Cory M. Johannessen,Jesse S. Boehm,So Young Kim,Sapana R. Thomas,Sapana R. Thomas,Leslie Wardwell,Laura A. Johnson,Laura A. Johnson,Caroline Emery,Nicolas Stransky,Alexandria P. Cogdill,Jordi Barretina,Jordi Barretina,Giordano Caponigro,Haley Hieronymus,Haley Hieronymus,Haley Hieronymus,Ryan R. Murray,Kourosh Salehi-Ashtiani,David E. Hill,Marc Vidal,Jean J. Zhao,Xiaoping Yang,Ozan Alkan,Sungjoon Kim,Jennifer L. Harris,Christine D. Wilson,Vic E. Myer,Peter Finan,David E. Root,Thomas M. Roberts,Todd R. Golub,Todd R. Golub,Keith T. Flaherty,Reinhard Dummer,Barbara L. Weber,William R. Sellers,Robert Schlegel,Jennifer A. Wargo,William C. Hahn,William C. Hahn,Levi A. Garraway,Levi A. Garraway +42 more
TL;DR: Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies.
Journal ArticleDOI
Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial
George D. Demetri,Peter Reichardt,Yoon-Koo Kang,Jean-Yves Blay,Piotr Rutkowski,Hans Gelderblom,Peter Hohenberger,Michael F. Leahy,Margaret von Mehren,Heikki Joensuu,Giuseppe Badalamenti,Martin E. Blackstein,Axel Le Cesne,Patrick Schöffski,Robert G. Maki,Sebastian Bauer,Binh Bui Nguyen,Jianming Xu,Toshirou Nishida,John Chung,Christian Kappeler,Iris Kuss,D. Laurent,Paolo G. Casali +23 more
TL;DR: The results of this study show that oral regorafenib can provide a significant improvement in progression-free survival compared with placebo in patients with metastatic GIST after progression on standard treatments.
Journal ArticleDOI
Tumour heterogeneity in the clinic
Philippe L. Bedard,Aaron R. Hansen,Aaron R. Hansen,Mark J. Ratain,Lillian L. Siu,Lillian L. Siu +5 more
TL;DR: A large number of cancer cells with unique genomes in the same patient may exist across different geographical regions of a tumour or evolve over time, called intratumour heterogeneity, and Sequencing technologies can be used to characterize intratumours heterogeneity at diagnosis, monitor clonal dynamics during treatment and identify the emergence of clinical resistance during disease progression.
Journal ArticleDOI
High-throughput oncogene mutation profiling in human cancer
Roman K. Thomas,Alissa C. Baker,Ralph M. Debiasi,Ralph M. Debiasi,Wendy Winckler,Wendy Winckler,Thomas LaFramboise,Thomas LaFramboise,William M. Lin,William M. Lin,Meng Wang,Meng Wang,Whei Feng,Whei Feng,Thomas Zander,Laura E. MacConnaill,Laura E. MacConnaill,Jeffrey C. Lee,Jeffrey C. Lee,Rick Nicoletti,Rick Nicoletti,Charlie Hatton,Charlie Hatton,Mary Goyette,Luc Girard,Kuntal Majmudar,Liuda Ziaugra,Kwok-Kin Wong,Stacey Gabriel,Rameen Beroukhim,Rameen Beroukhim,Michael Peyton,Jordi Barretina,Jordi Barretina,Amit Dutt,Amit Dutt,Caroline Emery,Heidi Greulich,Heidi Greulich,Kinjal Shah,Kinjal Shah,Hidefumi Sasaki,Adi F. Gazdar,John D. Minna,Scott A. Armstrong,Ingo K. Mellinghoff,F. Stephen Hodi,Glenn Dranoff,Paul S. Mischel,Timothy F. Cloughesy,Stan F. Nelson,Linda M. Liau,Kirsten D. Mertz,Kirsten D. Mertz,Mark A. Rubin,Holger Moch,Massimo Loda,William J. Catalona,Jonathan A. Fletcher,Sabina Signoretti,Frederic J. Kaye,Kenneth C. Anderson,George D. Demetri,Reinhard Dummer,Stephan N. Wagner,Meenhard Herlyn,William R. Sellers,William R. Sellers,Matthew Meyerson,Matthew Meyerson,Levi A. Garraway,Levi A. Garraway +71 more
TL;DR: High-throughput genotyping is adapted to query 238 known oncogene mutations across 1,000 human tumor samples and established robust mutation distributions spanning 17 cancer types, offering a new dimension in tumor genetics, where mutations involving multiple cancer genes may be interrogated simultaneously and in 'real time'.
References
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Journal ArticleDOI
Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors.
George D. Demetri,Margaret von Mehren,Charles D. Blanke,Annick D. Van den Abbeele,Burton L. Eisenberg,Peter J. Roberts,Michael Heinrich,David A. Tuveson,Samuel Singer,Milos J. Janicek,Jonathan A. Fletcher,Stuart G. Silverman,Sandra Silberman,Renaud Capdeville,Beate Kiese,Bin Peng,Sasa Dimitrijevic,Brian J. Druker,Christopher L. Corless,Christopher D.M. Fletcher,Heikki Joensuu +20 more
TL;DR: Imatinib induced a sustained objective response in more than half of patients with an advanced unresectable or metastatic gastrointestinal stromal tumor, indicating that inhibition of the KIT signal-transduction pathway is a promising treatment for advanced gastrointestinalStromal tumors, which resist conventional chemotherapy.
Journal ArticleDOI
PDGFRA Activating Mutations in Gastrointestinal Stromal Tumors
Michael Heinrich,Christopher L. Corless,Anette Duensing,Laura McGreevey,Chang Jie Chen,Nora E. Joseph,Samuel Singer,Diana J. Griffith,Andrea Haley,Ajia Town,George D. Demetri,Christopher D.M. Fletcher,Jonathan A. Fletcher,Jonathan A. Fletcher +13 more
TL;DR: Tumors expressing KIT or PDGFRA oncoproteins were indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression, suggesting KIT and PDGFra mutations appear to be alternative and mutually exclusive oncogenic mechanisms in GISTs.
Journal ArticleDOI
Kinase Mutations and Imatinib Response in Patients With Metastatic Gastrointestinal Stromal Tumor
Michael Heinrich,Christopher L. Corless,George D. Demetri,Charles D. Blanke,Margaret von Mehren,Heikki Joensuu,Laura McGreevey,Chang Jie Chen,Annick D. Van den Abbeele,Brian J. Druker,Beate Kiese,Burton L. Eisenberg,Peter J. Roberts,Samuel Singer,Christopher D.M. Fletcher,Sandra Silberman,Sasa Dimitrijevic,Jonathan A. Fletcher +17 more
TL;DR: Activating mutations of KIT or PDGFRA are found in the vast majority of GISTs, and the mutational status of these oncoproteins is predictive of clinical response to imatinib.
Journal ArticleDOI
Effect of the Tyrosine Kinase Inhibitor STI571 in a Patient with a Metastatic Gastrointestinal Stromal Tumor
Heikki Joensuu,Peter J. Roberts,Maarit Sarlomo-Rikala,Leif C. Andersson,Pekka Tervahartiala,David A. Tuveson,David A. Tuveson,Sandra Silberman,Renaud Capdeville,Sasa Dimitrijevic,Brian J. Druker,George D. Demetri +11 more
TL;DR: Gastrointestinal stromal tumors are a group of mesenchymal neoplasms that arise from precursors of the connective-tissue cells of the gastrointestinal tract that occur predominantly in middle-aged and older persons.
Journal ArticleDOI
Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial*
Jaap Verweij,Paolo G. Casali,John Zalcberg,A. Lecesne,Peter Reichardt,Jean-Yves Blay,Rolf D. Issels,Allan T. van Oosterom,Pancras C.W. Hogendoorn,Martine Van Glabbeke,Rossella Bertulli,Ian Judson +11 more
TL;DR: If response induction is the only aim of treatment, a daily dose of400 mg of imatinib is sufficient; however, a dose of 400 mg twice a day achieves significantly longer progression-free survival.
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