Drug Discovery and Development, Cancer Research Institute and Clinical and Health Sciences, University of South Australia, Australia.
Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, Australia.
Gynecol Oncol. 2020 Dec;159(3):827-838. doi: 10.1016/j.ygyno.2020.09.012. Epub 2020 Sep 18.
Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are involved in the initiation and progression of various cancers. Deregulation of the CDK4/6-cyclin D-retinoblastoma (Rb) pathway is common in ovarian cancer and is associated with an aggressive phenotype and poor prognosis. Patients with advanced ovarian cancer whose tumor demonstrates Rb-positivity, a low expression of p16 and overexpression of cyclin D1 are most likely to benefit from CDK4/6 inhibition.
Anti-proliferative activity and mechanistic investigations for CDDD2-94, employing palbociclib as comparator, were evaluated by MTT assay, cell cycle and apoptosis analysis, western blotting as well as senescence and colony formation assay. In vivo safety and efficacy studies were done in A2780 tumor-bearing nude mice. Combinations of CDDD2-94 with mTOR, MEK, PI3K or PARP inhibitors were evaluated in A2780 and OVCAR5 ovarian cancer cells.
Consistent with a CDK4-targeted mechanism, CDDD2-94 arrested the G1/G0 cell cycle, induced senescence and inhibited the proliferation of Rb-proficient ovarian cancer cells. CDDD2-94 exhibited synergistic anti-proliferative activities with mTOR, MEK, PI3K or PARP inhibitors. Importantly, unlike palbociclib which caused significant reductions in the number of lymphocytes and neutrophils, CDDD2-94 had little effect. CDDD2-94, as single agent and in combination with everolimus, delayed tumor growth and significantly increased survival of mice.
Given its high specificity in targeting CDK4 and excellent anti-tumor efficacy with low toxicity, CDDD2-94 has potential to be developed as a standalone agent or in combination with targeted therapeutics for the treatment of ovarian cancer.
细胞周期蛋白依赖性激酶 4 和 6（CDK4/6）是细胞周期的基本驱动因素，参与各种癌症的发生和进展。CDK4/6-细胞周期蛋白 D-视网膜母细胞瘤（Rb）通路的失调在卵巢癌中很常见，与侵袭性表型和不良预后相关。肿瘤中 Rb 阳性、p16 低表达和 cyclin D1 过表达的晚期卵巢癌患者最有可能受益于 CDK4/6 抑制。
采用 MTT 检测法、细胞周期和凋亡分析、Western blot 及衰老和集落形成检测法，评估 CDDD2-94 的抗增殖活性及作用机制，以 palbociclib 为对照。在 A2780 荷瘤裸鼠中进行体内安全性和疗效研究。在 A2780 和 OVCAR5 卵巢癌细胞中评价 CDDD2-94 与 mTOR、MEK、PI3K 或 PARP 抑制剂的联合用药。
与 CDK4 靶向机制一致，CDDD2-94 使 G1/G0 细胞周期停滞，诱导衰老并抑制 Rb 阳性卵巢癌细胞的增殖。CDDD2-94 与 mTOR、MEK、PI3K 或 PARP 抑制剂联合具有协同抗增殖活性。重要的是，与 palbociclib 显著降低淋巴细胞和中性粒细胞数量不同，CDDD2-94 几乎没有影响。CDDD2-94 单药及与依维莫司联合使用可延迟肿瘤生长，显著提高小鼠存活率。
鉴于其在靶向 CDK4 方面的高特异性和低毒性的优异抗肿瘤疗效，CDDD2-94 具有作为单药或与靶向治疗联合用于治疗卵巢癌的潜力。
