Resistance to EGF-R (erbB-1) and VEGF-R modulating agents

European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)
Wolfram C M Dempke, Volker Heinemann

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-1alpha and (4) HIF-1alpha-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 ...Continue Reading

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