Radiosensitization of brain metastasis by targeting c-MET

Abstract

Radiotherapy is the most widely used therapeutic modality in brain metastasis; however, it only provides palliation due to inevitable tumor recurrence. Resistance of tumor cells to ionizing radiation is a major cause of treatment failure. A critical unmet need in oncology is to develop rationale driven approaches that can enhance the efficacy of radiotherapy against metastatic tumor. Utilizing in vivo orthotopic primary tumor and brain metastasis models that recapitulate clinical situation of the patients with metastatic breast cancer, we investigated a molecular mechanism through which metastatic tumor cells acquire resistance to radiation. Recent studies have demonstrated that the hepatocyte growth factor (HGF)-c-Met pathway is essential for the pathologic development and progression of many human cancers such as proliferation, invasion and resistance to anticancer therapies. In this study, c-Met signaling activity as well as total c-Met expression was significantly upregulated in both breast cancer cell lines irradiated in vitro and ex vivo radio-resistant cells derived from breast cancer brain metastatic xenografts. To interrogate the role of c-Met signaling in radioresistance of brain metastasis, we evaluated the effects on tumor cell viability, clonogenicity, sensitivity to radiation, and in vitro/in vivo tumor growth after targeting c-Met by small-hairpin RNA (shRNA) or small-molecule kinase inhibitor (PF-2341066). Although c-Met silencing or radiation alone demonstrated a modest decrease in clonogenic growth of parental breast cancers and brain metastatic derivatives, combination of two modalities showed synergistic antitumor effects resulting in significant prolongation of overall survival in tumor-bearing mice. Taken together, optimizing c-Met targeting in combination with radiation is critical to enhance the effectiveness of radiotherapy in the treatments of brain metastasis. Traditional estimates of the incidence of brain metastasis in patients with breast cancer range from 10 to 16% of metastatic patients. The incidence will be likely rising due to several factors including the improved neuroimaging facilities, an aging population, and more effective systemic treatment for the primary disease. 1-5 Despite significant advances in understanding the molecular mechanisms of metastasis and development of new diagnostic, prognostic, and therapeutic tools, brain metastases constitute a major impact on morbidity and mortality, resulting in B7 months median survival with significant cognitive impairment at the time of presentation. [6][7][8][9] Up to now, standard treatment options for brain metastasis to aim locoregional control of cerebral metastases, palliation of symptoms, and prevention and/or improvement of functional deficits, include surgery, radiosurgery, and whole brain radiotherapy (WBRT) in various combinations. WBRT has been a critical component in the treatments of breast

Foretinib Enhances the Radiosensitivity in Esophageal Squamous Cell Carcinoma by Inhibiting Phosphorylation of c-Met

“…One mechanism by which foretinib enhanced radiosensitivity was related to changes in DNA damage repair following irradiation 32. DNA repair following double-stranded DNA breaks requires a variant histone protein called H2A.X.…”

Met and its ligand HGF are associated with clinical outcome in breast cancer

“…Previous studies have shown that Met protein expression and ligand-independent activation rose after ionising radiation, and silencing of MET led to increased radiosensitivity [1, 2, 14]. Therefore, in the present study, it was hypothesised that the HGF/Met axis drives radioresistance in breast cancer patients, and it was aimed to determine MET and HGF gene copy number, Met/HGF expression, and Met phosphorylation in breast tumours of patients randomised to receive either chemo- or radiotherapy, in order to study correlations with clinicopathological parameters and response to radiotherapy.…”

Receptor tyrosine kinase MET as potential target of multi‐kinase inhibitor and radiosensitizer sorafenib in HNSCC

“…With respect to EGFR, we have recently demonstrated that inhibition failed to induce significant cell death or robust radiosensitization in the cell lines used in this study. Although MET inhibition induces radiosensitization in other entities, it also failed to do so in our HNSCC cells pretreated for 2 hours with 2 different MET inhibitors. Additionally, effects of crizotinib or SU11274 on proliferation and cell survival without irradiation turned out to be very limited in the sub‐micromolar range, the concentration range where maximal MET inhibition was already achievable at the protein level (see Figure ).…”