Evaluation of: Lu KV, Chang JP, Parachoniak CA et al.
VEGF inhibits
tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex.
Cancer Cell 22(1), 21-35 (2012). In
glioblastoma, a well-characterized angiogenic target is
VEGF.
Bevacizumab is a humanized
monoclonal antibody that binds to
VEGF and was developed to inhibit the
VEGF signaling pathway. Based on promising results from clinical trials that
bevacizumab can prolong progression-free survival in recurrent
glioblastoma patients, the US FDA granted this
drug accelerated approval for the treatment of recurrent or progressive
glioblastoma; however, there has been no evidence that the overall median survival of patients is prolonged. More recently, Phase II clinical trials tested
bevacizumab in combination with traditional radiation and/or temozolamide in newly diagnosed
glioblastoma patients and again showed prolonged progression-free survival in these patients, but overall survival was not significantly changed. More importantly, there was evidence that
tumors resistant to or recurring after
bevacizumab treatment often showed a more aggressive phenotype. Due to the lack of effective post-
bevacizumab therapies, it has been suggested that treatment with
bevacizumab not be used until patients have developed late-stage recurrent
tumors. Under these circumstances, there is a timely need to uncover the mechanisms of resistance to
bevacizumab. In this article, Lu et al. reported a novel mechanism whereby
VEGF negatively regulates
tumor cell invasion by blocking MET phosphorylation in the MET/VEGFR2 complex. They showed that inhibiting the
VEGF pathway results in MET activation in
VEGF-knockout mouse models and in patients after bevacuzimub treatment, and that MET knockdown blocked the invasiveness of
VEGF knockout
tumors, suggesting that blocking the MET pathway can prevent post-
bevacizumab treatment
tumor recurrence, providing a strong rationale for using a combination of MET and
VEGF receptor inhibitors to treat
glioblastoma patients.