Targeting cell cycle and hormone receptor pathways in cancer.
Targeting cell cycle and hormone receptor pathways in cancer.
复制标题
作者：
细胞周期蛋白/细胞周期蛋白依赖性激酶(CDK)/视网膜母细胞瘤（RB）轴是细胞周期进入的关键调节剂，在许多人类癌症中是异常的。需要新的治疗干预节点，以延缓或对抗恶性肿瘤的发作。PD-0332991 （PD，一种有效的选择性CDK4/6抑制剂）的抗肿瘤特性和机制功能通过人前列腺癌（PCa）模型和原发肿瘤进行了研究。PD通过促进强劲的g1阻滞显著损害了PCa细胞的增殖能力。因此，G1- s细胞周期转变的关键调控因子被调节，包括G1周期蛋白D、E和a。随后的研究表明，PD能够在现有的激素方案下发挥作用，并与电离辐射合作，进一步抑制细胞生长。重要的是，它确定了PD是PD作用的关键介质。CDK4/6抑制的抗增殖作用通过减少增殖和延迟生长的PCa细胞异种移植物被揭示。最后，首次观察了PD对原发人前列腺切除术肿瘤组织外植体增殖的影响。该研究表明，选择性CDK4/6抑制，无论是单独使用还是联合使用，都会阻碍疾病进展所必需的关键增殖途径，并且RB状态是治疗效果的关键预后决定因素。综上所述，这些临床前研究结果确定了选择性靶向CDK4/6作为早期和晚期前列腺癌的真正治疗靶点，并强调了个性化医疗提高治疗反应的益处。
The cyclin/cyclin-dependent kinase (CDK)/retinoblastoma (RB)-axis is a critical modulator of cell cycle entry and is aberrant in many human cancers. New nodes of therapeutic intervention are needed that can delay or combat the onset of malignancies. The antitumor properties and mechanistic functions of PD-0332991 (PD; a potent and selective CDK4/6 inhibitor) were investigated using human prostate cancer (PCa) models and primary tumors. PD significantly impaired the capacity of PCa cells to proliferate by promoting a robust G1-arrest. Accordingly, key regulators of the G1-S cell cycle transition were modulated including G1 cyclins D, E and A. Subsequent investigation demonstrated the ability of PD to function in the presence of existing hormone-based regimens and to cooperate with ionizing radiation to further suppress cellular growth. Importantly, it was determined that PD is a critical mediator of PD action. The anti-proliferative impact of CDK4/6 inhibition was revealed through reduced proliferation and delayed growth using PCa cell xenografts. Finally, first-in-field effects of PD on proliferation were observed in primary human prostatectomy tumor tissue explants. This study shows that selective CDK4/6 inhibition, using PD either as a single-agent or in combination, hinders key proliferative pathways necessary for disease progression and that RB status is a critical prognostic determinant for therapeutic efficacy. Combined, these pre-clinical findings identify selective targeting of CDK4/6 as a bona fide therapeutic target in both early stage and advanced PCa and underscore the benefit of personalized medicine to enhance treatment response.
登录
查看更多内容
影响因子：
11.2
作者：
Cole AM;Myant K;Reed KR;Ridgway RA;Athineos D;Van den Brink GR;Muncan V;Clevers H;Clarke AR;Sicinski P;Sansom OJ
通讯作者：
Sansom OJ
影响因子：
50.3
作者：
Anders L;Ke N;Hydbring P;Choi YJ;Widlund HR;Chick JM;Zhai H;Vidal M;Gygi SP;Braun P;Sicinski P
通讯作者：
Sicinski P
影响因子：
11.2
作者：
Baughn, Linda B.;Di Liberto, Maurizio;Chen-Kiang, Selina
通讯作者：
Chen-Kiang, Selina
影响因子：
8
作者：
Dean, J. L.;Thangavel, C.;Knudsen, E. S.
通讯作者：
Knudsen, E. S.
影响因子：
11.5
作者：
Flaherty, Keith T.;LoRusso, Patricia M.;Schwartz, Gary K.
通讯作者：
Schwartz, Gary K.