骨肉瘤是最常见的原发性恶性骨肿瘤,治疗的主要方式和患者预后在近30年来相对停滞不前.随着越来越多骨肉瘤分子特征的揭示,骨肉瘤靶向治疗,如酪氨酸激酶抑制剂和细胞周期相关系列靶点抑制剂等的临床前研究与临床试验取得重要进展.周期检查点激酶1(checkpoint kinase 1,CHEK1)参与细胞DNA损伤应答,发挥着不可或缺的多种生物学功能,其特异性抑制剂的开发与研究在多种恶性肿瘤治疗领域的报道逐渐增多.骨肉瘤的多个亚群存在特征性改变,主要影响细胞周期和DNA损伤应答,特别是p53突变细胞可能对CHEK1抑制剂更敏感.设计靶向CHEK1相关途径的策略可能使患者受益.共济失调毛细血管扩张突变激酶(ataxia telangiectasia mutated,ATM)和(或)共济失调毛细血管扩张症和Rad3相关激酶(ataxia telangiectasia and rad3-related,ATR)抑制剂能干扰骨肉瘤细胞DNA损伤修复,使下游CHEK1相关分子成为潜在治疗靶点.抑制CHEK1能下调相关蛋白表达,抑制细胞增殖和修复,且与化疗药物联合效果明显.单用化疗药物效果常受限制,CHEK1抑制剂如Prexasertib可增强其对骨肉瘤细胞的杀伤作用,单独使用或与其他药物联合应用具有良好效果.将CHEK1抑制剂与其他细胞周期药物联合使用可能更具价值,或与其相关下游靶点抑制剂联合用药可提高疗效.此外,调控DNA损伤应答途径也可能与免疫治疗有关,靶向其相关的DNA损伤应答途径在骨肉瘤的治疗中具有潜在的应用前景.
Abstract
Osteosarcoma is the most common primary malignant bone tumor,yet treatment modalities and patient out-comes have remained relatively stagnant over the past three decades.Recently,with increasing insights into the molecular char-acteristics of osteosarcoma,targeted therapies,such as tyrosine kinase inhibitors and cell cycle-related inhibitors,have shown significant progress in both preclinical studies and clinical trials.Checkpoint kinase 1(CHEK1),a key player in DNA damage response,is involved in various critical biological functions,and the development of its specific inhibitors has gained attention in multiple fields of cancer treatment.Osteosarcoma,comprising multiple subtypes with distinct alterations in cell cycle and DNA damage response mechanisms,particularly exhibits increased sensitivity to CHEK1 inhibitors in p53 mutant cells.Target-ing the CHEK1-associated pathway holds promise for improving patient outcomes.Inhibition of ataxia telangiectasia mutated(ATM)and/or ataxia telangiectasia and Rad3-related(ATR)pathways impairs DNA damage repair in osteosarcoma cells,identi-fying downstream molecules linked to CHEK1 as potential therapeutic targets.Suppression of CHEK1 activity leads to downreg-ulation of related protein expression and inhibits cell proliferation and repair processes,an effect that is notably enhanced when combined with chemotherapeutic agents.Although single-agent chemotherapy often produces limited results,the use of CHEK1 inhibitors such as Prexasertib enhances cytotoxic effects against osteosarcoma cells,either as monotherapy or in combination regimens,demonstrating robust efficacy.Co-administration of CHEK 1 inhibitors with other cell cycle modulators or downstream target antagonists could further optimize treatment outcomes.Furthermore,modulating DNA damage response pathways may have implications for immunotherapy.This review systematically summarizes recent research on the CHEK 1-related pathway in osteosarcoma and emphasizes that targeting the DNA damage response pathway related to CHEK 1 may be a promising strategy for osteosarcoma treatment with broad prospects.
维普
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