Gene Expression Profile Identifies Tyrosine Kinase c-Met as a Targetable Mediator of Antiangiogenic Therapy Resistance

Abstract

Purpose To identify mediators of glioblastoma anti-angiogenic therapy resistance and target these mediators in xenografts. Experimental Design We performed microarray analysis comparing bevacizumab-resistant glioblastomas (BRGs) to pre-treatment tumors from the same patients. We established novel xenograft models of anti-angiogenic therapy resistance to target candidate resistance mediator(s). Results BRG microarray analysis revealed upregulation versus pre-treatment of receptor tyrosine kinase c-Met, which underwent further investigation because of its prior biologic plausibility as a bevacizumab resistance mediator. BRGs exhibited increased hypoxia versus pre-treatment in a manner correlating with their c-Met upregulation, increased c-Met phosphorylation, and increased phosphorylation of c-Met-activated focal adhesion kinase (FAK) and STAT3. We developed two novel xenograft models of anti-angiogenic therapy resistance. In the first model, serial bevacizumab treatment of an initially responsive xenograft generated a xenograft with acquired bevacizumab resistance, which exhibited upregulated c-Met expression versus pre-treatment. In the second model, a BRG-derived xenograft maintained refractoriness to the MRI tumor vasculature alterations and survival-promoting effects of bevacizumab. Growth of this BRG-derived xenograft was inhibited by a c-Met inhibitor. Transducing these xenograft cells with c-Met shRNA inhibited their invasion and survival in hypoxia, disrupted their mesenchymal morphology, and converted them from bevacizumab-resistant to bevacizumab-responsive. Engineering bevacizumab-responsive cells to express constitutively active c-Met caused these cells to form bevacizumab-resistant xenografts. Conclusion These findings support the role of c-Met in survival in hypoxia and invasion, features associated with anti-angiogenic therapy resistance; and growth and therapeutic resistance of xenografts resistant to anti-angiogenic therapy. Therapeutically targeting c-Met could prevent or overcome anti-angiogenic therapy resistance.

The Novel VEGF Receptor/MET–Targeted Kinase Inhibitor TAS-115 Has MarkedIn VivoAntitumor Properties and a Favorable Tolerability Profile

“…The HGF-mediated change in the expression of these factors promotes tumor angiogenesis. These insights might explain the action of HGF/MET signaling as an endogenous resistance factor for VEGFR-targeted inhibitors (40,41). Furthermore, HGF/MET signaling activity is greater under hypoxic conditions after VEGFR-targeted inhibitors treatment than under normoxia, and hypoxiainduced HGF/MET signaling activity may reinforce tumor progression and metastasis (42).…”

Orphan drugs in glioblastoma multiforme: a review

“…78,79 Therefore, targeting this factor in combination with antiangiogenic therapy might be effective in order to overcome resistance, and results from clinical trials are awaited.…”

MET/HGF pathway activation as a paradigm of resistance to targeted therapies

“…In glioblastoma multiforme models, Jahangiri and colleagues conducted gene expression studies suggesting that in bevacizumab-resistant tumors, MET is one of the most overexpressed genes and that genetic ablation could reverse resistance and reduce tumor cell invasion and tumor cell survival (55). Other studies suggested that dual VEGFR and MET blockade reduces metastasis and improves survival in several preclinical models (56).…”