Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL-7647.
OBJECTIVE
Agents inhibiting the epidermal growth factor receptor (EGFR) have shown clinical benefit in a subset of non-small cell lung cancer patients expressing amplified or mutationally activated EGFR. However, responsive patients can relapse as a result of selection for EGFR gene mutations that confer resistance to ATP competitive EGFR inhibitors, such as erlotinib and gefitinib. We describe here the activity of EXEL-7647 (XL647), a novel spectrum-selective kinase inhibitor with potent activity against the EGF and vascular endothelial growth factor receptor tyrosine kinase families, against both wild-type (WT) and mutant EGFR in vitro and in vivo.


METHODS
The activity of EGFR inhibitors against WT and mutant EGFRs and their effect on downstream signal transduction was examined in cellular assays and in vivo using A431 and MDA-MB-231 (WT EGFR) and H1975 (L858R and T790M mutant EGFR) xenograft tumors.


RESULTS
EXEL-7647 shows potent and long-lived inhibition of the WT EGFR in vivo. In addition, EXEL-7647 inhibits cellular proliferation and EGFR pathway activation in the erlotinib-resistant H1975 cell line that harbors a double mutation (L858R and T790M) in the EGFR gene. In vivo efficacy studies show that EXEL-7647 substantially inhibited the growth of H1975 xenograft tumors and reduced both tumor EGFR signaling and tumor vessel density. Additionally, EXEL-7647, in contrast to erlotinib, substantially inhibited the growth and vascularization of MDA-MB-231 xenografts, a model which is more reliant on signaling through vascular endothelial growth factor receptors.


CONCLUSIONS
These studies provide a preclinical basis for clinical trials of XL647 in solid tumors and in patients bearing tumors that are resistant to existing EGFR-targeted therapies.
Gendreau
Steven B
SB
Exelixis, Inc., South San Francisco, California 94083, USA.
Ventura
Richard
R
Keast
Paul
P
Laird
A Douglas
AD
Yakes
F Michael
FM
Zhang
Wentao
W
Bentzien
Frauke
F
Cancilla
Belinda
B
Lutman
Jeffery
J
Chu
Felix
F
Jackman
Lisa
L
Shi
Yongchang
Y
Yu
Peiwen
P
Wang
Jing
J
Aftab
Dana T
DT
Jaeger
Christopher T
CT
Meyer
Stephanie M
SM
De Costa
Anushka
A
Engell
Kelly
K
Chen
Jason
J
Martini
Jean-Francois
JF
Joly
Alison H
AH
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000187:drug effects* / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D053961:Azabicyclo Compounds; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; C571826:XL647; D000077156:Gefitinib