PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib.
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.
Engelman
Jeffrey A
JA
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
Zejnullahu
Kreshnik
K
Gale
Christopher-Michael
CM
Lifshits
Eugene
E
Gonzales
Andrea J
AJ
Shimamura
Takeshi
T
Zhao
Feng
F
Vincent
Patrick W
PW
Naumov
George N
GN
Bradner
James E
JE
Althaus
Irene W
IW
Gandhi
Leena
L
Shapiro
Geoffrey I
GI
Nelson
James M
JM
Heymach
John V
JV
Meyerson
Matthew
M
Wong
Kwok-Kin
KK
Jänne
Pasi A
PA
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*
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