title: Overcoming cetuximab resistance in Ewing's sarcoma by inhibiting lactate dehydrogenase-A.
abstract: Ewing's sarcoma, the second most common type of malignant bone tumor, generally occurs in children and young adults. The current treatment of Ewing's sarcoma comprises systemic anti‑cancer chemotherapy with complete surgical resection. However, the majority of patients with Ewing's sarcoma develop resistance to chemotherapy. The present study revealed an oncogenic role of lactate dehydrogenase‑A (LDHA) in the resistance of Ewing's sarcoma to cetuximab. LDHA was shown to be upregulated at the protein and mRNA level in cetuximab‑resistant Ewing's sarcoma tissues and a cell line. In addition, a link between LDHA‑induced glycolysis and cetuximab resistance in Ewing's sarcoma cells was revealed. Of note, inhibition of LDHA by either small interfering RNA or LDHA inhibitor oxamate significantly re‑sensitized cetuximab‑resistant cells to cetuximab. Combined treatment with LDHA inhibitor and cetuximab synergistically reduced the viability of cetuximab-resistant cells through the suppression of LDHA. The present study revealed a novel mechanism of cetuximab resistance from the perspective of cancer‑cell metabolism and provided a sensitization approach, which may aid in the development of anti-chemoresistance strategies for the treatment of cetuximab-resistant Ewing's sarcoma.
authors.affiliation: Department of Orthopedics, Tianjin Third Central Hospital, Tianjin 300170, P.R. China.
authors.forename: Jiaxin
authors.initials: J
authors.lastname: Fu
authors.affiliation: Department of Orthopedics, Tianjin Third Central Hospital, Tianjin 300170, P.R. China.
authors.forename: Han
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Orthopedics, Tianjin Third Central Hospital, Tianjin 300170, P.R. China.
authors.forename: Chenxuan
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Orthopedics, Tianjin Third Central Hospital, Tianjin 300170, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Orthopedics, Tianjin Third Central Hospital, Tianjin 300170, P.R. China.
authors.forename: Lianping
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Department of Orthopedics, Tianjin Third Central Hospital, Tianjin 300170, P.R. China.
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Tian
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006019:Glycolysis; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics; D000080864:Lactate Dehydrogenase 5; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D012512:Sarcoma, Ewing / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007527:Isoenzymes; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D000068818:Cetuximab