title: PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib.
abstract: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib are effective treatments for a subset of non-small cell lung cancers. In particular, cancers with specific EGFR-activating mutations seem to be the most sensitive to these agents. However, despite their initial response, such cancers almost invariably develop resistance. In 50% of such cancers, a secondary EGFR mutation, T790M, has been identified that renders gefitinib and erlotinib ineffective inhibitors of EGFR kinase activity. Thus, there is a clinical need to develop novel EGFR inhibitors that can effectively inactivate T790M-containing EGFR proteins. In this study, we evaluate the effectiveness of a novel compound, PF00299804, an irreversible pan-ERBB inhibitor. The results from these studies show that PF00299804 is a potent inhibitor of EGFR-activating mutations as well as the EGFR T790M resistance mutation both in vitro and in vivo. Additionally, PF00299804 is a highly effective inhibitor of both the wild-type ERBB2 and the gefitinib-resistant oncogenic ERBB2 mutation identified in lung cancers. These preclinical evaluations support further clinical development of PF00299804 for cancers with mutations and/or amplifications of ERBB family members.
authors: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
authors: Jeffrey A
authors: JA
authors: Engelman
authors: Kreshnik
authors: K
authors: Zejnullahu
authors: Christopher-Michael
authors: CM
authors: Gale
authors: Eugene
authors: E
authors: Lifshits
authors: Andrea J
authors: AJ
authors: Gonzales
authors: Takeshi
authors: T
authors: Shimamura
authors: Feng
authors: F
authors: Zhao
authors: Patrick W
authors: PW
authors: Vincent
authors: George N
authors: GN
authors: Naumov
authors: James E
authors: JE
authors: Bradner
authors: Irene W
authors: IW
authors: Althaus
authors: Leena
authors: L
authors: Gandhi
authors: Geoffrey I
authors: GI
authors: Shapiro
authors: James M
authors: JM
authors: Nelson
authors: John V
authors: JV
authors: Heymach
authors: Matthew
authors: M
authors: Meyerson
authors: Kwok-Kin
authors: KK
authors: Wong
authors: Pasi A
authors: PA
authors: Jänne
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002455:Cell Division; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D066246:ErbB Receptors / Q000187:drug effects / Q000235:genetics*; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms; D051379:Mice; D008819:Mice, Nude; D018739:Oncogene Proteins v-erbB / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology*; D052999:Quinazolinones / Q000627:therapeutic use*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; C413364:ERBIN protein, human; D018739:Oncogene Proteins v-erbB; D011799:Quinazolines; D052999:Quinazolinones; C525726:dacomitinib; D066246:ErbB Receptors; D000077156:Gefitinib