Vascular Endothelial Growth Factor Receptor-1 Contributes to Resistance to Anti–Epidermal Growth Factor Receptor Drugs in Human Cancer Cells
Purpose: The resistance to selective EGFR inhibitors involves the activation of alternative signaling pathways, and Akt activation and VEGF induction have been described in EGFR inhibitor–resistant tumors. Combined inhibition of EGFR and other signaling proteins has become a successful therapeutic a...
Saved in:
Published in | Clinical cancer research Vol. 14; no. 16; pp. 5069 - 5080 |
---|---|
Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Philadelphia, PA
American Association for Cancer Research
15.08.2008
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | Purpose: The resistance to selective EGFR inhibitors involves the activation of alternative signaling pathways, and Akt activation
and VEGF induction have been described in EGFR inhibitor–resistant tumors. Combined inhibition of EGFR and other signaling
proteins has become a successful therapeutic approach, stimulating the search for further determinants of resistance as basis
for novel therapeutic strategies.
Experimental Design: We established human cancer cell lines with various degrees of EGFR expression and sensitivity to EGFR inhibitors and analyzed
signal transducers under the control of EGFR-dependent and EGFR-independent pathways.
Results: Multitargeted inhibitor vandetanib (ZD6474) inhibited the growth and the phosphorylation of Akt and its effector p70S6 kinase
in both wild-type and EGFR inhibitor–resistant human colon, prostate, and breast cancer cells. We found that the resistant
cell lines exhibit, as common feature, VEGFR-1/Flt-1 overexpression, increased secretion of VEGF and placental growth factor,
and augmented migration capabilities and that vandetanib is able to antagonize them. Accordingly, a new kinase assay revealed
that in addition to VEGF receptor (VEGFR)-2, RET, and EGFR, vandetanib efficiently inhibits also VEGFR-1. The contribution
of VEGFR-1 to the resistant phenotype was further supported by the demonstration that VEGFR-1 silencing in resistant cells
restored sensitivity to anti-EGFR drugs and impaired migration capabilities, whereas exogenous VEGFR-1 overexpression in wild-type
cells conferred resistance to these agents.
Conclusions: This study shows that VEGFR-1 contributes to anti-EGFR drug resistance in different human cancer cells. Moreover, vandetanib
inhibits VEGFR-1 activation, cell proliferation, and migration, suggesting its potential utility in patients resistant to
EGFR inhibitors. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-07-4905 |