Progress in the systemic control of osteosarcoma has been limited over the past decades thus indicating the urgent clinical need for the development of novel treatment strategies. Therefore, we have recently developed new preclinical models to study promising novel agents for the treatment of pediatric osteosarcoma. The checkpoint kinase (chk) inhibitor prexasertib (LY2606368) and its salt form (LSN2940930) have recently been shown to be active in adult and pediatric malignancies, including sarcoma. We have now tested the potency of prexasertib in clonogenic survival assays in two new lines of primary patient‐derived osteosarcoma cells and in two established osteosarcoma cell lines as a single agent and in combination with cisplatin and the poly ADP‐ribose polymerase (PARP) inhibitor talazoparib. Prexasertib alone results in strongly reduced clonogenic survival at low nanomolar concentrations and acts by affecting cell cycle progression, induction of apoptosis and induction of double‐stranded DNA breakage at concentrations that are well below clinically tolerable and safe plasma concentrations. In combination with cisplatin and talazoparib, prexasertib acts in a synergistic fashion. Chk1 inhibition by prexasertib and its combination with the DNA damaging agent cisplatin and the PARP‐inhibitor talazoparib thus emerges as a potential new treatment option for pediatric osteosarcoma which will now have to be tested in preclinical primary patient derived in vivo models and clinical studies.

中文翻译：

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Prexasertib (LY2606368) 通过诱导原发性患者来源的骨肉瘤细胞凋亡来减少克隆存活，并与顺铂和他拉佐帕尼具有协同作用。

过去几十年来，骨肉瘤的系统控制进展有限，因此表明临床迫切需要开发新的治疗策略。因此，我们最近开发了新的临床前模型来研究有前景的治疗儿童骨肉瘤的新型药物。检查点激酶 (chk) 抑制剂 prexasertib (LY2606368) 及其盐形式 (LSN2940930) 最近被证明对成人和儿童恶性肿瘤（包括肉瘤）具有活性。我们现在已经在两个新的患者来源的骨肉瘤细胞系和两个已建立的骨肉瘤细胞系中测试了 prexasertib 作为单药以及与顺铂和聚 ADP 核糖聚合酶 (PARP) 抑制剂联合使用在克隆生存测定中的效力塔拉佐帕尼。单独使用 Prexasertib 会在低纳摩尔浓度下显着降低克隆存活率，并在远低于临床可耐受和安全血浆浓度的浓度下通过影响细胞周期进程、诱导细胞凋亡和诱导双链 DNA 断裂发挥作用。prexasertib 与顺铂和他拉佐帕尼联合使用，可发挥协同作用。因此，prexasertib 抑制 Chk1 及其与 DNA 损伤剂顺铂和 PARP 抑制剂他拉佐帕尼的组合成为儿科骨肉瘤的潜在新治疗选择，目前必须在临床前原发性患者体内模型和临床研究中进行测试。