Abstract
In an effort to improve the survival of cancer patients, new therapeutic approaches
focusing on the molecular mechanisms that mediate tumour cell growth or survival have
gained much attention. In particular, EGF-R and VEGF/VEGF-R have been extensively
investigated as targets for anti-neoplastic therapy. Agents that selectively target
EGF-R, erbB-2, VEGF-R-2 or VEGF have shown promising activity in clinical trials,
and several are now approved for use in selected cancer indications. However, all
patients ultimately develop resistance to these drugs. Thus, there is a great need
to understand how patients become resistant to effective therapies for these cancers
since this approach may lead to improvements in therapies that target EGF-R and VEGF/VEGF-R.
Pre-clinical studies have begun to shed light on the mechanisms of resistance to anti-angiogenetic
drugs and to date four mechanisms of resistance have been identified (1) upregulation
of bFGF, (2) overexpression of MMP-9, (3) increased levels of SDF-1α and (4) HIF-1α-induced
recruitment of bone marrow-derived CD45+ myeloid cells. In addition, the molecular
mechanisms of resistance to EGF-R modulating agents can be attributed to several general
processes: (1) activation of alternative tyrosine kinase inhibitors that bypass the
EGF-R pathway (e.g. c-MET and IGF-1R), (2) increased angiogenesis, (3) constitutive
activation of downstream mediators (e.g. PTEN and K-ras) and (4) the existence of
specific EGF-R mutations. K-ras mutations have been significantly associated with
a lack of response to EGF-R tyrosine kinase inhibitors in patients with NSCLC and
with a lack of response to cetuximab or to panitumumab in patients with advanced colorectal
cancer. The identification of these resistance mechanisms has led to clinical trials
using newly designed targeted therapies that can overcome resistance and have shown
promise in laboratory studies. Ongoing research efforts will likely continue to identify
additional resistance mechanisms, and these findings will hopefully translate into
effective therapies for different cancers.
Keywords
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Article info
Publication history
Published online: January 05, 2009
Accepted:
November 20,
2008
Received in revised form:
November 18,
2008
Received:
September 23,
2008
Identification
Copyright
© 2008 Elsevier Ltd. Published by Elsevier Inc. All rights reserved.
