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抑制剂还可以与抗HER-2药物、PD-L1、PD-L1抑制剂或其他靶向药物联合,联合治疗在一定程度上克服了CDK4/6抑制剂的耐药情况,并提高了治疗疗效,为乳腺癌患者的精准治疗带来了福音。     

CDK4/6抑制剂治疗消化道肿瘤的研究进展

摘 要：CDK4/6抑制剂（CDK4/6 inhibitors,CDK4/6i）通过调控Rb/E2F通路,诱导细胞周期停滞,抑制细胞增殖,发挥抗肿瘤作用,被FDA批准用于乳腺癌的治疗,并在多个瘤种中被广泛研究。在消化道肿瘤相关研究中,CDK4/6i表现出较好的抗肿瘤活性,并可与化疗、靶向治疗、免疫治疗和放疗等产生良好的协同效果。全文现就CDK4/6i近年在消化道肿瘤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抑制剂治疗三阴性乳腺癌的研究进展

细胞周期的调控机制在肿瘤的发生、发展中发挥着重要作用。多项研究表明,在雌激素受体阳性、人类表皮生长因子受体阴性的乳腺癌患者中,细胞周期蛋白依赖性激酶4/6（cyclin-dependent kinase 4/6,CDK4/6）抑制剂具有较好的疗效,然而其在三阴性乳腺癌患者中的疗效仍需进一步探讨。Cyclin D-CDK4/6-INK4-Rb-E2F信号通路因具有调控细胞周期检查点的作用,被认为是乳腺癌潜在的治疗靶点。寻找三阴性乳腺癌与CDK4/6抑制剂关联的生物标志物,探究合理的药物配伍,筛选能从中获益的靶向人群,对临床工作具有重要意义。对CDK4/6抑制剂在三阴性乳腺癌的研究进展进行综述,探讨其应用前景及优化手段。     

CDK4/6抑制剂联合放疗治疗34例晚期乳腺癌的安全性评估

[目的]评估晚期激素受体阳性/人表皮生长因子受体-2阴性(hormone-receptor positive,HR+/human epidermal growth factor receptor-2-,HER2-)乳腺癌使用细胞周期蛋白依赖性激酶4/6抑制剂(cyclin-dependent kinases 4/6 inhibitors,CDK4/6i)期间联合放疗的安全性。[方法]收集2021年7月至2023年6月34例CDK4/6i±放疗的Ⅲ～Ⅳ期HR+/HER2-乳腺癌的不良事件(adverse events,AEs）。[结果]最常见的AEs是血液学毒性：32.4%患者出现了≥3级骨髓抑制,26.5%出现1～2级骨髓抑制。29.4%出现1～2级非血液学毒性,包括消化道反应（恶心、腹泻、纳差）、疲劳、肝功能异常、骨骼肌肉不适、食管黏膜炎、皮疹等。放疗期间无患者需要减少CDK4/6i剂量或停药。[结论]晚期HR+/HER2-乳腺癌放疗期间使用CDK4/6i没有明显增加毒性反应,安全可控。     

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。     

肿瘤的光遗传学治疗

光遗传学技术应用遗传学和光的方法刺激和控制生物组织中特定细胞的功能。自从2005年报道用光照射视蛋白精准控制神经活性以来,光遗传学在肿瘤治疗中的应用初见端倪,其作用机制包括操纵神经元活动、解除免疫抑制、改变细胞内外电压、控制细胞力、调控信号转导、遗传和表观遗传调节以及筛选抗肿瘤药物。未来将通过光刺激改变肿瘤行为,肿瘤光遗传学治疗前途光明。     

CDK4/6 Inhibition as a therapeutic strategy in breast cancer: palbociclib,ribociclib, and abemaciclib

With 40,920 American women expected to die from breast cancer in 2018 and global health estimates that more than 508,000 women died in 2011 from this disease, the identification of novel therapeutic strategies for the treatment of breast cancer cannot be ignored. A breakthrough class of cancer drugs that has emerged in recent years and has had an impact in the treatment of breast cancer are the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, with palbociclib the first in class to have received regulatory approval for breast cancer. In this article we will compare and contrast three CDK4/6 inhibitors - palbociclib, ribociclib and abemaciclib - that have received regulatory approval for the treatment of metastatic breast cancer. Ribociclib and abemaciclib developed after the success of palbociclib represent examples of "me-too" therapies increasingly being deployed in oncology.     

CDK4/6 Inhibitors Impair Recovery from Cytotoxic Chemotherapy in Pancreatic Adenocarcinoma

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CKIs对人乳腺癌细胞侵袭转移的影响

目的利用CKI肽类似物抑制CDK激酶活性,以明确CKI对人乳腺癌细胞的作用,探讨其对乳腺癌细胞体外侵袭转移的影响。方法利用作用于CDK4／CDK6的CKI肽类似物p20和p21,分别干预人乳腺癌MDA-MB-231细胞株24h。然后应用细胞与纤维连结蛋白黏附实验测定肿瘤细胞黏附率,通过单层细胞划痕实验观察细胞转染前后迁移能力的变化,Transwell侵袭实验检测细胞体外侵袭力。结果人乳腺癌MDA-MB-231细胞株经CKI肽类似物p20和p21分别干预后,细胞黏附、迁移及侵袭能力明显减弱。结论 CDK4/CDK6激酶对乳腺癌侵袭转移过程具有重要的作用。CKI肽类似物可以抑制乳腺癌MDA-MB-231细胞的黏附、侵袭和迁移。因此CKI肽类似物可能阻抑肿瘤细胞的转移,显示此类细胞穿膜肽在恶性肿瘤治疗上的潜在作用。     

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。     

Drug-drug interactions in breast cancer patients treated with CDK4/6 inhibitors

CDK4/6 inhibitors are a new class of anticancer drugs used for the treatment of women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. Polypharmacy is a well-known problem in advanced cancer causing potential drug-drug interactions (DDIs), which, in turn, may limit the therapeutic value of CDK4/6 inhibitors. Therefore, understanding the mechanisms underlying potential DDIs in patients taking CDK4/6 inhibitors may be useful in decision-making processes and represent an important step towards treatment personalization. The present review is aimed at describing the potential DDIs that might occur in breast cancer patients receiving CDK4/6 inhibitors based on direct evidence from the literature and mechanistic considerations tailored on specific class of drugs used in combination.     

Outcomes and toxicity of concurrent CDK4/6 inhibitor and locoregional radiotherapy for patients with de novo metastatic breast cancer

The objective of the present study was to assess the outcomes and toxicity of patients treated with concurrent administration of CDK4/6 inhibitors (CDK4/6i) and locoregional radiation therapy (RT), including the breast with a boost or the thoracic wall after mastectomy and the regional lymph node areas. We retrospectively analyzed data from 27 patients with hormone receptor-positive, HER2-negative de novo metastatic breast cancer treated with CDK4/6i and concomitant locoregional RT in 2017/2022. Survival rates were calculated by Kaplan-Meier method. Prognostic factors were tested with log-rank test. CDK4/6i was used as the first systemic metastatic treatment for all the patients, and the median overall treatment time was 26 months. The median time from initiation of CDK4/6i to the start of RT was 10 months (IQR: 7-14 months). The median duration of concomitant CDK4/6i and RT administration was 21 days (IQR: 14.5-23 days). After a median follow-up of 19 months (IQR: 14-36 months), 1 patient died, 11/27 had distant metastases and 1 patient had local recurrence, respectively. The 1- and 3-years progression-free survival (PFS) were 61.4% (95% CI: 45.1%-83.7%) and 53.7% (35.8%-80.5%), respectively. The acute toxicities most observed during RT were neutropenia (44%) and dermatitis (37%). Dermatitis was significantly more frequent in patients with large target volumes (CTV > 911 cc and PTV > 1285 cc). CDK4/6i had to be discontinued in five patients during RT (due to toxicity in three cases and disease progression in two cases). One patient has developed grade 2 late pulmonary fibrosis. Finally, our study demonstrated that concurrent administration of locoregional RT and CDK4/6i did not induce severe late toxicity for most patients.     

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。