Expression and clinical relevance of MET and ALK in Ewing sarcomas

Because novel therapeutic options are limited in Ewing sarcomas (ES), we investigated the expression, genetic aberrations and clinical relevance of MET and anaplastic lymphoma kinase (ALK) in ES and determined the relevance of targeting these receptors. MET and ALK protein expression was determined immunohistochemically in 31 (50 samples) and 36 (59 samples) ES patients, respectively. Samples included primary tumors, postchemotherapy resections, metastases and relapses. MET and ALK RTK domains were sequenced in respectively 33 and 32 tumors. Five ES cell lines were treated in vitro with the MET/ALK‐inhibitor crizotinib, the ALK‐inhibitor NVP‐TAE684 or the MET‐inhibitor cabozantinib and analyzed by MTT assays. Modest to high MET and ALK expression was detected in the majority of ES (86 and 69%, respectively). ALK expression was significantly lower in postchemotherapy resections compared to paired untreated primary tumors (p = 0.031, z = −2.310, n = 11). In primary tumors (n = 20), membranous MET expression significantly correlated with a poor overall survival (OS) (60 vs. 197 months, p = 0.014). There was a trend toward a poor event‐free survival (67 vs. 111 months, p = 0.078) and OS (88 vs. 128 months, p = 0.074) in patients with highest ALK levels (n = 29). ALK or MET RTK domain aberrations were demonstrated in 5/32 (16%) and 3/33 (9%) tumors, respectively. Crizotinib (IC50 1.22–3.59 μmol/L), NVP‐TAE684 (IC50 0.15–0.79 μmol/L) and cabozantinib (IC50 2.69–8.27 μmol/L) affected ES cell viability in vitro. Altogether, our data suggest that MET and ALK are potential novel therapeutic targets in ES and targeting these receptors may be of great interest to rationally design future studies in ES. What's new? The protein MET helps spur cell proliferation as well as metastasis and angiogenesis. MET expression correlates with aggressive disease and poor prognosis. The current study looks at the role of MET and another receptor, ALK, in Ewing sarcomas, a bone malignancy that mostly hits adolescents. The authors tested MET and ALK levels in patients with Ewing sarcoma and correlated the expression levels with outcomes. They found that both MET and ALK are abundantly expressed in Ewing sarcomas, and agents that inhibit these proteins slowed the growth of tumor cells in vitro, suggesting that MET and ALK inhibitors could be a promising line of inquiry for treating Ewing sarcomas.