Research progress of checkpoint kinase 1 in targeted therapy of osteosarcoma
10.3760/cma.j.cn121113-20240313-00152
- VernacularTitle:检查点激酶1在骨肉瘤靶向治疗中的研究进展
- Author:
Jianfei MA
1
;
Jiatong LI
;
Guanning SHANG
Author Information
1. 中国医科大学附属盛京医院骨与软组织肿瘤科，沈阳 110022
- Keywords:
Osteosarcoma;
Checkpoint Kinase 1;
Molecular targeted therapy;
DNA damage response
- From:
Chinese Journal of Orthopaedics
2024;44(16):1118-1124
- CountryChina
- Language:Chinese
-
Abstract:
Osteosarcoma is the most common primary malignant bone tumor, yet treatment modalities and patient outcomes have remained relatively stagnant over the past three decades. Recently, with increasing insights into the molecular characteristics 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. Targeting 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, identifying downstream molecules linked to CHEK1 as potential therapeutic targets. Suppression of CHEK1 activity leads to downregulation 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 CHEK1 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 CHEK1-related pathway in osteosarcoma and emphasizes that targeting the DNA damage response pathway related to CHEK1 may be a promising strategy for osteosarcoma treatment with broad prospects.
