BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models.
Daizong Li,Lauren Ambrogio,Lauren Ambrogio,Takeshi Shimamura,Shigeto Kubo,Masaya Takahashi,Lucian R. Chirieac,Robert F. Padera,Geoffrey I. Shapiro,Anke Baum,Frank Himmelsbach,Wolfgang J. Rettig,Matthew Meyerson,Matthew Meyerson,F. Solca,Heidi Greulich,Heidi Greulich,K-K Wong +17 more
Reads0
Chats0
TLDR
It is shown that BIBW2992, an anilino-quinazoline designed to irreversibly bind EGFR and HER2, potently suppresses the kinase activity of wild-type and activated EGFRand HER2 mutants, including erlotinib-resistant isoforms.Abstract:
Genetic alterations in the kinase domain of the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) patients are associated with sensitivity to treatment with small molecule tyrosine kinase inhibitors. Although first-generation reversible, ATP-competitive inhibitors showed encouraging clinical responses in lung adenocarcinoma tumors harboring such EGFR mutations, almost all patients developed resistance to these inhibitors over time. Such resistance to first-generation EGFR inhibitors was frequently linked to an acquired T790M point mutation in the kinase domain of EGFR, or upregulation of signaling pathways downstream of HER3. Overcoming these mechanisms of resistance, as well as primary resistance to reversible EGFR inhibitors driven by a subset of EGFR mutations, will be necessary for development of an effective targeted therapy regimen. Here, we show that BIBW2992, an anilino-quinazoline designed to irreversibly bind EGFR and HER2, potently suppresses the kinase activity of wild-type and activated EGFR and HER2 mutants, including erlotinib-resistant isoforms. Consistent with this activity, BIBW2992 suppresses transformation in isogenic cell-based assays, inhibits survival of cancer cell lines and induces tumor regression in xenograft and transgenic lung cancer models, with superior activity over erlotinib. These findings encourage further testing of BIBW2992 in lung cancer patients harboring EGFR or HER2 oncogenes.read more
Citations
More filters
Journal ArticleDOI
Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations
Lecia V. Sequist,James Chih-Hsin Yang,Nobuyuki Yamamoto,Kenneth J. O'Byrne,Vera Hirsh,Tony Mok,Sarayut Lucien Geater,Sergey Orlov,Chun-Ming Tsai,Michael Boyer,Wu Chou Su,Jaafar Bennouna,Terufumi Kato,Vera Gorbunova,Ki Hyeong Lee,Riyaz Shah,Dan Massey,Victoria Zazulina,Mehdi Shahidi,Martin Schuler +19 more
TL;DR: The LUX-Lung 3 study as mentioned in this paper investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epIDERmal growth factors receptor 2 (HER2/ERbB2), and ErbbB4 and has wide-spectrum preclinical activity against EGFR mutations.
Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations
Lecia V. Sequist,James Chih-Hsin Yang,Nobuyuki Yamamoto,Kenneth J. O'Byrne,Vera Hirsh,Tony Mok,Sarayut Lucien Geater,Sergey Orlov,Chun-Ming Tsai,Michael Boyer,Wu Chou Su,Jaafar Bennouna,Terufumi Kato,Vera Gorbunova,Ki Hyeong Lee,Riyaz Shah,Dan Massey,Victoria Zazulina,Mehdi Shahidi,Martin Schuler +19 more
TL;DR: Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.
Journal ArticleDOI
AZD9291 in EGFR Inhibitor–Resistant Non–Small-Cell Lung Cancer
Pasi A. Jänne,James Chih-Hsin Yang,Dong Wan Kim,David Planchard,Yuichiro Ohe,Suresh S. Ramalingam,Myung-Ju Ahn,Sang We Kim,Wu Chou Su,Leora Horn,Daniel Haggstrom,Enriqueta Felip,Joo Hang Kim,Paul Frewer,Mireille Cantarini,Kathryn H. Brown,Paul A. Dickinson,Serban Ghiorghiu,Malcolm R Ranson +18 more
TL;DR: AZD9291 was highly active in patients with lung cancer with the EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors.
Journal ArticleDOI
Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial
Yi-Long Wu,Caicun Zhou,Chengping Hu,Jifeng Feng,Shun Lu,Yunchao Huang,Wei Li,Mei Hou,Jian Hua Shi,Kye Young Lee,Chong-Rui Xu,Dan Massey,MI-Young Kim,Yang Shi,Sarayut Lucien Geater +14 more
TL;DR: Afatinib significantly improves progression-free survival with a tolerable and manageable safety profile in Asian patients with EGFR mutation-positive advanced lung NSCLC and should be considered as a first-line treatment option for this patient population.
Journal ArticleDOI
AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer
Darren Cross,Susan Ashton,Serban Ghiorghiu,Cath Eberlein,Caroline A. Nebhan,Paula J. Spitzler,Jonathon P. Orme,M. Raymond V. Finlay,Richard A. Ward,Martine J. Mellor,Gareth D Hughes,Amar Rahi,Vivien Jacobs,Monica Red Brewer,Eiki Ichihara,Jing Sun,Hailing Jin,Peter Ballard,Katherine Al-Kadhimi,Rachel Rowlinson,Teresa Klinowska,Graham Richmond,Mireille Cantarini,Dong Wan Kim,Malcolm R Ranson,William Pao +25 more
TL;DR: A novel structurally distinct third-generation EGFR TKI that irreversibly and selectively targets both sensitizing and resistant T790M(+) mutant EGFR while harboring less activity toward wild-type EGFR is reported.
References
More filters
Journal ArticleDOI
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib
Thomas J. Lynch,Daphne W. Bell,Raffaella Sordella,Sarada Gurubhagavatula,Ross A. Okimoto,Brian W. Brannigan,Patricia L. Harris,Sara M. Haserlat,Jeffrey G. Supko,Frank G. Haluska,David N. Louis,David C. Christiani,Jeff Settleman,Daniel A. Haber +13 more
TL;DR: 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, and these mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor.
Journal ArticleDOI
EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.
J. Guillermo Paez,Pasi A. Jänne,Pasi A. Jänne,Jeffrey C. Lee,Sean Tracy,Heidi Greulich,Heidi Greulich,Stacey Gabriel,Paula Herman,Frederic J. Kaye,Neal I. Lindeman,Titus J. Boggon,Katsuhiko Naoki,Hidefumini Sasaki,Yoshitaka Fujii,Michael J. Eck,William R. Sellers,William R. Sellers,William R. Sellers,Bruce E. Johnson,Bruce E. Johnson,Matthew Meyerson,Matthew Meyerson +22 more
TL;DR: Results suggest that EGFR mutations may predict sensitivity to gefitinib, and treatment with the EGFR kinase inhibitor gefitsinib causes tumor regression in some patients with NSCLC, more frequently in Japan.
Journal ArticleDOI
Cancer statistics, 2006.
Ahmedin Jemal,Rebecca L. Siegel,Elizabeth Ward,Taylor Murray,Jiaquan Xu,Carol Smigal,Michael J. Thun +6 more
TL;DR: The American Cancer Society estimated the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute and mortality data from National Center for Health Statistics as discussed by the authors.
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
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
TL;DR: 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.
Related Papers (5)
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
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib
Gefitinib or Chemotherapy for Non–Small-Cell Lung Cancer with Mutated EGFR
Makoto Maemondo,Akira Inoue,Kunihiko Kobayashi,Shunichi Sugawara,Satoshi Oizumi,Hiroshi Isobe,Akihiko Gemma,Masao Harada,Hirohisa Yoshizawa,Ichiro Kinoshita,Yuka Fujita,Shoji Okinaga,Haruto Hirano,Kozo Yoshimori,Toshiyuki Harada,Takashi Ogura,Masahiro Ando,Hitoshi Miyazawa,Tomoaki Tanaka,Yasuo Saijo,Koichi Hagiwara,Satoshi Morita,Toshihiro Nukiwa +22 more
EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.
J. Guillermo Paez,Pasi A. Jänne,Pasi A. Jänne,Jeffrey C. Lee,Sean Tracy,Heidi Greulich,Heidi Greulich,Stacey Gabriel,Paula Herman,Frederic J. Kaye,Neal I. Lindeman,Titus J. Boggon,Katsuhiko Naoki,Hidefumini Sasaki,Yoshitaka Fujii,Michael J. Eck,William R. Sellers,William R. Sellers,William R. Sellers,Bruce E. Johnson,Bruce E. Johnson,Matthew Meyerson,Matthew Meyerson +22 more