Research Institute for Clinical Oncology, Saitama Cancer Center, 818 Komuro, Ina, Saitama 362-0806, Japan.
Saga International Carbon Particle Beam Radiation Cancer Therapy Center, Saga HIMAT Foundation, 3049 Harakoga-Machi, Saga 841-0071, Japan.
Biomolecules. 2021 May 18;11(5):750. doi: 10.3390/biom11050750.
Unrestrained proliferation is a common feature of malignant neoplasms. Targeting the cell cycle is a therapeutic strategy to prevent unlimited cell division. Recently developed rationales for these selective inhibitors can be subdivided into two categories with antithetical functionality. One applies a "brake" to the cell cycle to halt cell proliferation, such as with inhibitors of cell cycle kinases. The other "accelerates" the cell cycle to initiate replication/mitotic catastrophe, such as with inhibitors of cell cycle checkpoint kinases. The fate of cell cycle progression or arrest is tightly regulated by the presence of tolerable or excessive DNA damage, respectively. This suggests that there is compatibility between inhibitors of DNA repair kinases, such as PARP inhibitors, and inhibitors of cell cycle checkpoint kinases. In the present review, we explore alterations to the cell cycle that are concomitant with altered DNA damage repair machinery in unfavorable neuroblastomas, with respect to their unique genomic and molecular features. We highlight the vulnerabilities of these alterations that are attributable to the features of each. Based on the assessment, we offer possible therapeutic approaches for personalized medicine, which are seemingly antithetical, but both are promising strategies for targeting the altered cell cycle in unfavorable neuroblastomas.
不受限制的增殖是恶性肿瘤的共同特征。针对细胞周期是防止无限细胞分裂的一种治疗策略。最近开发的这些选择性抑制剂的合理理由可以分为两类，具有相反的功能。一种是在细胞周期中施加“刹车”以停止细胞增殖，例如细胞周期激酶抑制剂。另一种是“加速”细胞周期以引发复制/有丝分裂灾难，例如细胞周期检查点激酶抑制剂。细胞周期进展或停滞的命运受到可容忍或过度 DNA 损伤的存在的严格调节。这表明，DNA 修复激酶抑制剂（如 PARP 抑制剂）与细胞周期检查点激酶抑制剂之间存在兼容性。在本综述中，我们探讨了不利神经母细胞瘤中伴随改变的 DNA 损伤修复机制的细胞周期改变，这些改变与它们独特的基因组和分子特征有关。我们强调了这些改变的脆弱性，这些脆弱性归因于每个改变的特征。基于评估，我们为个性化医学提供了可能的治疗方法，这些方法看似相反，但都是针对不利神经母细胞瘤中改变的细胞周期的有前途的策略。
