CDK4/6抑制剂在乳腺癌治疗中的研究进展

细胞增殖、生长和分裂等过程受到细胞周期的严格调控,其调控机制在肿瘤的发生发展中发挥重要作用。近年来,多项研究显示,细胞周期蛋白依赖性激酶4和6（CDK4/6）抑制剂对于雌激素受体阳性或人类表皮生长因子受体阳性的乳腺癌患者具有较好的疗效,然而其在三阴性乳腺癌患者中的作用仍存在争议,故探究相关分子标志物以进一步筛选最能从该治疗中获益的乳腺癌人群对临床具有重要意义。此外视网膜母细胞瘤基因（Rb）也在乳腺癌中扮演关键角色,而cyclin D-CDK4/6-Rb信号通路因具有调控细胞周期限制点的作用,被认为是乳腺癌潜在的治疗靶点。本文将对CDK4/6抑制剂在乳腺癌治疗中的研究进展作一综述。     

CDK4/6抑制剂在乳腺癌治疗中的研究进展

CDK4/6抑制剂与内分泌治疗的组合策略被越来越多地应用于晚期乳腺癌患者的治疗中.然而,CDK4/6抑制剂不仅仅用于ER阳性、HER2阴性晚期乳腺癌患者的治疗中,其研究应用也扩展到了其他的乳腺癌类型中.本文旨在阐述CDK4/6抑制剂的耐药机制和进展后的后续治疗,以及其在三阴性乳腺癌、HER2阳性乳腺癌、肿瘤免疫和生活质...     

CDK4/6抑制剂治疗乳腺癌的研究进展

对于HR+/HER-2-乳腺癌患者来说,内分泌治疗扮演着非常重要的角色.长久以来,医学工作者对于此类患者的内分泌耐药机制以及相关治疗方法的讨论也层出不穷.近年来,CDK4/6抑制剂为HR+患者的带来了福音,CDK4/6抑制剂单药治疗与联合内分泌治疗已经用于晚期乳腺癌的治疗.除了内分泌治疗之外,CDK4/6抑制剂还可以与...     

CDK4/6抑制剂联合内分泌治疗晚期乳腺癌研究进展

摘 要：近年来,多项研究显示细胞周期蛋白依赖性激酶4和6( CDK4/6) 抑制剂对于激素受体阳性晚期乳腺癌患者具有较好的疗效,甚至可改善内分泌耐药问题。相关研究表明CDK4/6抑制剂联合内分泌治疗在临床应用中极具前景。     

CDK4/6抑制剂耐药机制的研究进展

细胞周期依赖性激酶4/6（cyclin-dependent kinase 4/6,CDK4/6)抑制剂能作用于过度活化的CDK4/6,恢复正常细胞周期,并通过触发免疫,改变肿瘤微环境等发挥抗肿瘤作用。目前,CDK4/6抑制剂的问世极大地改善了激素受体阳性（hormone receptor-positive,HR+）、人表皮生长因子受体2阴性（human epidermal growth factor receptor 2-negative,HER2-)晚期乳腺癌患者的预后,使无进展生存期(progression-free-survival,PFS)增加近一倍,且不良反应可控。尽管如此,这类患者最终仍会因CDK4/6抑制剂耐药而出现疾病进展。CDK4/6抑制剂的耐药机制十分复杂,尚未完全明确。预测其早期耐药或治疗敏感的生物标记物也有待确定。本文对CDK4/6抑制剂治疗的作用机制及耐药机制进行梳理和总结,并对疾病进展后的治疗策略作简要讨论。     

CDK4/6抑制剂联合mTOR抑制剂在乳腺癌中的作用机制

CDK-RB-E2F通路和PI3K-AKT-mTOR通路对乳腺癌耐药机制起到了关键作用。通过对两个通路的研究发现,在治疗激素受体阳性的乳腺癌时,CDK4/6抑制剂与内分泌药物联合使用可以提高患者的生存率,mTOR抑制剂也显示出抗肿瘤的实力。最近的研究表明,mTOR抑制剂和CDK4/6抑制剂联合使用可以进一步抑制CDK-RB-E2F通路激活,协同控制肿瘤细胞增殖。同时发现CDK4/6抑制剂耐药患者的CDK-RB-E2F通路重新激活,仍对mTOR抑制剂敏感。还有研究表明CDK4/6抑制剂和mTOR抑制剂可以通过自噬作用协同控制肿瘤的发生。本文针对两药联合在乳腺癌中的作用机制进行综述。     

CDK4/6抑制剂联合内分泌治疗晚期乳腺癌

内分泌治疗因疗效显著并具有安全性,是激素受体阳性(HR+)晚期乳腺癌患者的主要治疗方法。近年来内分泌领域发展迅速,如何延迟或逆转内分泌耐药及内分泌治疗新药物成为临床研究关注的焦点。研究发现,内分泌治疗耐药可能与CDK-RB-E2F通路有关,针对该通路的细胞周期蛋白依赖性激酶(CDK)4/6抑制剂可显著延缓HR+晚期乳腺癌患者内分泌耐药。CDK4/6抑制剂与内分泌药物联合使用,可提高HR+晚期乳腺癌患者的治疗客观缓解率,并可显著改善无进展生存期(PFS)。现就CDK4/6抑制剂的作用机制、药物有效性和安全性及相关临床试验做一综述。     

CDK4/6抑制剂抗肿瘤作用研究进展

细胞周期素依赖性蛋白激酶4/6（cyclin-dependent kinases 4/6,CDK4/6）与细胞周期蛋白D（cyclin D）结合,通过调节细胞G1-S期转换,成为细胞周期调控机制的核心部分。CDK4/6-cyclin D-INK4-Rb通路的异常活化将会导致癌细胞失控性生长,该通路的异常存在于多种恶性肿瘤中,因此CDK4/6成为潜在的治疗靶点。本文对CDK4/6的作用机制,及主要几种CDK4/6抑制剂的研究进展进行综述,旨在探讨CDK4/6抑制剂在恶性肿瘤治疗中的应用前景及优化手段。     

CDK4/6抑制剂在乳腺癌中的研究进展

摘 要：细胞周期的失调是肿瘤生长和转移的典型标志之一,通过CDK抑制剂重新建立细胞周期的调控在肿瘤靶向治疗的发展中已经成为有吸引力的方向。三种选择性靶向CDK4/6的口服药物已经被研发：palbociclib、abemaciclib和LEE011。当前的研究表明CDK4/6抑制剂与内分泌药物联合治疗激素受体阳性乳腺癌是一个新的标准。全文就细胞周期调控、乳腺癌中cyclinD-CDK4/6-Rb途径及相关蛋白p16和survivin的异常表现、CDK4/6抑制剂的相关临床试验及其结果进行总结。     

CDK4/6 inhibition in early and metastatic breast cancer: A review

Breast cancer (BC) is responsible for 14% of cancer-related deaths in women [1]. Cyclin-dependent kinase (CDK) 4/6 inhibitors are a new class of selective drugs, offering an effective and tolerable treatment. CDK4/6 inhibitors induce cell cycle arrest in the G1 phase, and may thereby prevent tumour progression. Three CDK4/6 inhibitors have been tested in clinical BC trials: palbociclib, ribociclib, and abemaciclib. The Food and Drug Administration (FDA) and European Commission (EMA) have approved palbociclib for the treatment of patients HR+ HER2- locally advanced or metastatic BC (aBC) in combination with an aromatase inhibitor as initial therapy in postmenopausal women or in combination with fulvestrant in women who have received prior endocrine therapy. Ribociclib has been approved by the FDA in combination with an aromatase inhibitor as initial therapy for postmenopausal women with HR+ HER2- aBC. Moreover, CDK4/6 inhibitors have shown promising results in the (neo)adjuvant setting. In this review, the principal completed and ongoing clinical trials in aBC are reviewed for both the metastatic as (neo)adjuvant setting. Tables will provide a complete overview of the ongoing clinical trials. At last, the future perspectives of these CDK4/6 inhibitors are discussed.     

CDK4/6抑制剂在激素受体阳性进展期乳腺癌治疗中的研究进展

内分泌治疗因其兼具良好的疗效及安全性,是激素受体阳性进展期乳腺癌患者的重要治疗手段。近年来内分泌领域进展迅速,很多新型药物相继出现,其中包括多种可以逆转或延迟内分泌耐药的周期蛋白依赖性激酶(cyclin-dependent kinase,CDK)4/6抑制剂。CDK4/6抑制剂联合内分泌治疗可为激素受体阳性进展期乳腺癌患者带来生存获益、延迟至化疗时间,正逐渐改变国内外激素受体阳性进展期乳腺癌的治疗模式。本文将就CDK4/6抑制剂在激素受体阳性进展期乳腺癌中的治疗进展进行综述。     

Mechanisms of therapeutic CDK4/6 inhibition in breast cancer

Cyclin dependent kinase (CDK) 4/6 inhibitors have advanced the treatment of metastatic breast cancer by targeting the cell cycle machinery, interrupting intracellular and mitogenic hormone signals that stimulate proliferation of malignant cells. Preclinical evidence demonstrated that derangements of cyclin D1, CDK4/6, and retinoblastoma expression are common in breast cancer, and suggested a therapeutic benefit from interrupting this axis required for cell cycle progression. Studies of cell lines and animal models of breast cancer have demonstrated the complex interplay between the cell cycle and estrogen receptor and human epidermal growth receptor 2 signaling, which informs our understanding of synergistic use of CDK4/6 inhibitors with endocrine therapy, as well as mechanisms of resistance to endocrine therapy. Interestingly, estrogen receptor activity leads to upregulation of cyclin D1 expression, but the estrogen receptor is also in turn activated by cyclin D1, independent of estrogen binding. Early CDK inhibitors were nonspecific and limited by systemic toxicities, while the current generation of CDK4/6 inhibitors have shown promise in the treatment of hormone receptor-positive breast cancer. Preclinical investigations of the three CDK4/6 inhibitors approved by the US Food and Drug Administration (palbociclib, ribociclib, and abemaciclib) lend further insight into their mechanism of action, which will hopefully inform the future use and refinement of these therapies. Finally, we summarize evidence for additional novel CDK4/6 inhibitors currently in development.     

三阴性乳腺癌雄激素受体研究进展

三阴性乳腺癌(triple-negative breast cancer,TNBC)是一组异质性疾病,缺乏有效的靶向治疗,预后差。近年来研究证实,雄激素受体(androgen receptor,AR)在TNBC的发生、发展中起重要作用。AR成为TNBC中研究的热点,并可能成为TNBC靶向治疗的新选择。该研究将对三阴乳腺癌与AR表达进行相关阐述,并提供在TNBC中靶向AR信号通路的新视野。     

Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review

Deregulation of the cyclin D-CDK4/6-INK4-RB pathway leading to uncontrolled cell proliferation, is frequently observed in breast cancer. Currently, three selective CDK4/6 inhibitors have been FDA approved: palbociclib, ribociclib and abemaciclib. Despite promising clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitors has limited the success of these treatments; therefore, the development of various strategies to overcome this resistance is of great importance. We highlight the various mechanisms that are directly or indirectly responsible for resistance to CDK4/6 inhibitors, categorizing them into two broad groups; cell cycle-specific mechanisms and cell cycle-nonspecific mechanisms. Elucidation of the diverse mechanisms through which resistance to CDK4/6 inhibitors occurs, may aid in the design of novel therapeutic strategies to improve patient outcomes. This review summarizes the currently available knowledge regarding mechanisms of resistance to CDK4/6 inhibitors, and possible therapeutic strategies that may overcome this resistance as well.     

三阴性乳腺癌中miRNA-124表达与E-钙黏蛋白及雄激素受体的关系

目的 研究三阴性乳腺癌(Triple-negative breast cancer,TNBC)中miRNA-124(miR-124)的表达与E-钙黏蛋白(E-cadherin)及雄激素受体(Androgen receptor,AR)的关系。方法 采用RT-PCR在TNBC组织和癌旁正常乳腺组织中检测miR-124的表达,免疫组化检测TNBC中E-cadherin及雄激素受体(AR)的表达。结果 与癌旁正常乳腺组织相比,TNBC组织中miR-124表达明显降低(P＜0.05);TNBC组织中,miR-124表达与组织分级、E-cadherin表达有关(P＜0.05),与AR表达无关(P＞0.05)。结论 在TNBC中,miR-124可能通过调节E-cadherin的表达发挥抑癌作用。