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Advances in Clinical Medicine
Vol. 11  No. 12 ( 2021 ), Article ID: 47238 , 8 pages
10.12677/ACM.2021.1112851

CDK4/6抑制剂在HR+/HER-2−乳腺癌中耐药机制及生物标志物研究进展

袁晓莉，王振波*

滨州医学院附属医院肿瘤科，山东 滨州

收稿日期：2021年11月13日；录用日期：2021年12月3日；发布日期：2021年12月16日

摘要

CDK4/6抑制剂(CDK4/6i)联合内分泌治疗是激素受体阳性、HER-2阴性(HR+/HER-2−)晚期乳腺癌的主要治疗手段。然而，无论是原发性还是获得性的耐药性总是会发生，导致治疗失败和癌症进展。随着CDK4/6抑制剂应用的推广，研究者发现其并非对所有ER+乳腺癌患者有效，缺乏可靠的预测疗效或筛选患者群体的生物标志物是限制其临床应用的主要挑战。本文将对CDK4/6抑制剂在乳腺癌治疗中的耐药机制和对CDK4/6抑制剂生物标志物进行综述。

关键词

乳腺癌，CDK4/6抑制剂，耐药，生物标志物

Research Progress on Resistance Mechanism and Biomarker of CDK4/6 Inhibitor in HR+/HER-2− Breast Cancer

Xiaoli Yuan, Zhenbo Wang*

Department of Oncology, Binzhou Medical University Hospital, Binzhou Shandong

Received: Nov. 13th, 2021; accepted: Dec. 3rd, 2021; published: Dec. 16th, 2021

ABSTRACT

CDK4/6 inhibitor (CDK4/6i) combined with endocrine therapy is the primary treatment for hormone receptor-positive, HER-2-negative (HR+/HER-2−) advanced breast cancer. However, drug resistance, whether primary or acquired, always occurs, leading to treatment failure and cancer progression. As the use of CDK4/6 inhibitors has expanded, researchers have found that they are not effective in all patients with ER+ breast cancer, and the lack of reliable biomarkers to predict efficacy or to screen patient populations is a major challenge limiting their clinical use. In this paper, we will review the latest research progress of the mechanism of CDK4/6 inhibitor resistance in breast cancer treatment and CDK4/6 inhibitor biomarkers.

Keywords:Breast Cancer, CDK4/6 Inhibitor, Resistance, Biomarkers

Copyright © 2021 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

乳腺癌是全世界女性中最常见的恶性肿瘤之一，也是大多数癌症相关死亡的主要原因 [1]。在所有乳腺癌中，雌激素受体阳性(ER+)和HER-2阴性肿瘤所占比例最大，约为65%~70% [2]，因此，内分泌治疗是乳腺癌有效的治疗方式。细胞周期蛋白依赖性激酶(Cyclin dependent kinase, CDK) 4/6抑制剂联合内分泌治疗能显著提高ER+/HER-2−乳腺癌患者的无进展生存期(PFS) [3]。因此，CDK4/6抑制剂成为乳腺癌治疗的重要靶点之一。CDK4/6抑制剂(Palbociclib、Ribocilib和Abemaciclib)用于ER+/HER-2−乳腺癌患者的一线治疗现已被美国食品药品监督管理局批准 [4] [5] [6]。

然而由于原发或获得性耐药的产生，CDK4/6抑制剂在临床中的应用受到了很大限制，且目前尚缺乏能够预测其治疗效果的可靠生物标志物。精准医学时代中，基于生物信息学、组织芯片和二代测序等技术手段筛选预测标志物，有助于准确预测疗效，对实现个体化治疗和提示临床治疗效果具有重要意义。本文主要综述了CDK4/6抑制剂在乳腺癌治疗中的耐药机制和CDK4/6抑制剂的疗效预测生物标志物。

2. CDK4/6抑制剂在乳腺癌中的作用及机制

细胞分裂是正常细胞在严格控制下的常见细胞过程，以防意外增殖，这通常是癌症的原因。参与细胞周期调控的途径很多，CDK家族是细胞分裂调控中最重要的蛋白家族之一 [7] (见图1)。在细胞周期的G1期，CDK4/6与细胞周期素D (Cyclin D)相互作用形成Cyclin D-CDK4/6复合物，使Rb蛋白磷酸化 [8] [9]。失活的Rb与转录因子E2F紧密结合，Rb的磷酸化从Rb-E2F复合物中释放E2F，随后诱导E2F靶基因上调，启动DNA合成，导致细胞周期进入S期 [9] [10] [11]。

在乳腺癌和其他恶性肿瘤中，观察到Cyclin D1-CDK4/6-Rb信号级联的异常调节，并促进了不受控制的细胞增殖 [12] [13]。近15%的乳腺癌被检测到Cyclin D基因CCND1 (Cyclin D1)的扩增，并且研究发现在高达50%的原发性ER+乳腺癌和高分化肿瘤中Cyclin D1在mRNA和蛋白水平上的表达上调 [14] [15]。在乳腺癌细胞系中，Cyclin D的诱导启动了细胞周期过程，并增加了从G1期到S期的细胞数量 [16]，体内研究表明，Cyclin D过表达使得转基因小鼠乳腺细胞发生异常增殖，促进了乳腺癌的发生发展 [17]。在许多癌症中，Cyclin D1的过度表达与预后不良有关，并且常常与转移增加有关 [14] [18] [19]。同样，散发性乳腺癌中CDK4的过度表达与肿瘤细胞的高增殖能力呈正相关 [20]。CDK6在5个鳞癌细胞系中活性升高 [21]，抑制Cyclin D3-CDK6导致肿瘤细胞凋亡 [22]。所有这些证据表明，CDK4/6和Cyclin D可能是肿瘤治疗的潜在靶点。

图注：MAPK、PI3K和ER等上游信号通路的激活促进了细胞周期蛋白D-CDK4/6复合体的形成，使Rb蛋白磷酸化。随着Rb的磷酸化，E2F从Rb-E2F复合物中解离出来。作为一种转录因子，释放的E2F启动DNA合成，导致细胞周期从G1期进入S期。CDK4/6抑制剂(Palbociclib、ribociclib和abemaciclib)可阻止CDK4/6的激活，导致细胞周期阻滞于G1期 [7]。

Figure 1. Mechanism of CDK4/6 inhibitors and possible combined therapy with CDK4/6 inhibitors

图1. CDK4/6抑制剂的作用机制及可能与CDK4/6抑制剂的联合治疗

3. CDK4/6抑制剂的耐药机制

CDK4/6抑制剂的发现改善了ER+/HER-2−乳腺癌的预后，也可能使HER-2+乳腺癌和其他实体肿瘤受益。然而，并非所有患者对CDK4/6抑制剂都有反应，甚至对CDK4/6抑制剂敏感的患者也可能产生耐药 [23]。目前CDK4/6抑制剂的耐药机制尚不清楚。

3.1. Rb的缺失

成视网膜细胞瘤基因(Retinoblastoma gene, Rb)的缺失已经成为一种内在和获得性耐药的机制。Rb作为CDK4/6的靶点，被认为是CDK4/6靶向治疗敏感性的最重要的生物标志物之一 [24]。临床前研究证明，在接受帕博西尼(Palbociclib)或瑞博西尼(Ribociclib)治疗的晚期乳腺癌患者中，Rb功能丧失 [25]。随着疾病的进展，检测到Rb1体细胞突变 [26]，提示Rb突变可能与对CDK4/6抑制剂的获得性耐药有关。然而，在Paloma-3试验中，研究者并未发现CDK4/6抑制剂与Rb1表达之间的相互作用，因此需要对Rb通路进行更广泛深入的分析。

3.2. Cyclin E1、CDK2、CDK4、CDK6的过表达

除Cyclin D-CDK4/6复合物外，Cyclin E-CDK2复合物也可通过磷酸化Rb释放E2F [27]，从而使肿瘤细胞产生耐药性。Cyclin E1是CDK2的一个调节亚单位，在G1/S检查点启动DNA复制的过程中起着中心作用。由于Cyclin E-CDK2磷酸化事件位于Cyclin D-CDK4/6介导的磷酸化事件的下游，Cyclin E1的过表达使得CDK4/6的抑制在诱导G1期阻滞或随后的生长抑制方面无效。因此，Cyclin E1水平高的肿瘤很可能对CDK4/6的抑制具有内在的抵抗力 [28]。

作为促进细胞周期从G1期进入S期的三种间期CDK之一，CDK4是一个公认的原癌基因 [29]。在有丝分裂刺激下，CDK4和CDK6与Cyclin D形成活性复合物，通过直接磷酸化启动Rb和相关蛋白的失活 [30]。Rb蛋白的磷酸化导致它们从转录抑制复合物中解离，从而激活依赖于E2F的基因表达，从而促进细胞周期的G1-S期转变，并最终推动增殖 [29] [30]。

3.3. p16扩增

p16INK4A是一种固有的肿瘤抑制因子，可以与CDK4/6结合，破坏Cyclin D-CDK4/6复合物的形成 [31] [32] [33]。在致癌应激过程中观察到p16的过度表达。当p16过表达与Rb缺失同时发生时，由于Rb功能障碍，获得了对CDK4/6抑制剂的耐药性 [34]。在Rb存在的情况下，p16的过表达由于CDK4的降低而表现出对CDK4/6抑制剂的耐药性 [35]。

3.4. 血清TK1水平

胸苷激酶-1 (Thymidine kinase 1, TK1)是细胞周期的关键调节因子，在S/G2期高表达，催化DNA前体合成 [36]。血清TK1水平和活性在实体肿瘤中升高，包括乳腺癌、肺癌和结直肠癌 [37]。在乳腺癌患者中，高TK1水平和活性与肿瘤大小和预后不良有关 [38] [39]。在HR+/HER-2−转移性乳腺癌(HR+/HER-2− MBC)患者中，基线TK1活性降低与PFS延长相关，治疗1个月后TK1活性降低与PFS明显改善相关 [40]，提示TK1是HR+/HER-2− MBC中有意义的潜在治疗靶点。ECLIPS是一项前瞻性的药物遗传学研究，旨在确定对Palbociclib加ET (来曲唑或氟维司群)敏感/耐药的预测性生物标志物。结果表明，进展期患者治疗前TK1mRNA拷贝数/mL明显高于治疗3个月后(1200 vs 3350拷贝/mL，P = 0.01)，提示TK1mRNA拷贝数/mL与CDK4/6抑制剂获得性耐药有关 [41]。

3.5. FAT1的缺失

FAT1是一种潜在的肿瘤抑制因子，是与河马信号通路相互作用的钙粘蛋白超家族成员之一，最近发现它可以调节CDK6的表达，其缺失可能介导了对CDK4/6抑制剂的耐药性。FAT1基因敲除导致河马信号通路下调和CDK6过度表达。对348例接受基于CDK4/6抑制剂治疗的患者的活检组织进行基因测序显示，在这些患者中，大约有6%的患者FAT1发生了突变。因此，FAT1缺失可能是CDK4/6抑制剂耐药的有效预测因子 [42]。

3.6. FGFR的扩增

成纤维细胞生长因子受体(fibroblast growth factor receptor, FGFRs)家族包括四个高度保守的跨膜受体酪氨酸激酶(FGFR1-4)和一个能够结合成纤维细胞生长因子配体(FGFs)但缺乏细胞内激酶结构域的受体(FGFR5，也称为FGFRL1)。FGF介导重要的生理机制，如组织和新陈代谢的动态平衡、内分泌功能和伤口修复。在许多肿瘤类型中，FGF信号轴的失控与肿瘤发生、肿瘤进展和抗癌治疗耐药有关。尽管已有多项研究提出异常的FGFR信号通路可作为各种肿瘤的潜在治疗靶点，但临床上抗FGFR治疗的疗效各不相同 [43]。

据报道，在激素受体阳性的乳腺癌中有近15%发生FGFR1扩增，并且与不良预后有关。FGFR1与CDK4/6抑制剂的耐药性以及内分泌抵抗有关。FGFR1扩增通过持续的MAPK活化诱导内分泌抗性，通过激活PI3K-AKT和RAS/MEK/ERK信号通路，并以ER依赖性和独立的方式促进CCND1表达导致对CDK4/6抑制剂产生耐药性 [43]。

3.7. PTEN的缺失

PTEN是指人第10号染色体缺失的磷酸酶及张力蛋白同源的基因，其缺失可导致对CDK4/6抑制剂的原发和获得性耐药。从机制上讲，PTEN的缺失使p27 (细胞周期素依赖性激酶抑制物)被排除在细胞核外，进而导致CDK4和CDK2的激活增加，最终通过维持Rb的磷酸化来降低对CDK4/6抑制剂的敏感性，从而减轻细胞周期停滞 [44]。

3.8. PI3K/AKT/mTOR通路

在ER+乳腺癌中，mTOR通路经常被过度激活，丝氨酸/苏氨酸激酶mTOR整合了多种细胞信号，包括有丝分裂原和营养信号，以控制细胞增殖、细胞周期和细胞大小。mTOR激酶形成两个不同的多蛋白复合物，称为mTORC1和mTORC2。调节mTOR的输入信号之一是PI3K/AKT通路，它可以激活mTORC1复合体。CDK4/6抑制剂通过磷酸肌醇依赖性蛋白激酶1 (PDPK1)使AKT磷酸化，并激活Ribociclib耐药乳腺癌细胞中PI3K/AKT通路，PI3K能使Cyclin D1的表达增加，从而使乳腺癌细胞对CDK4/6抑制剂产生耐药性 [45]。

此外，研究还发现CDK4/6抑制剂耐药细胞株重新激活了CDK-Rb-E2F通路，但对mTORC1/2抑制仍然敏感，这表明mTORC1/2抑制剂可能是CDK4/6抑制剂耐药患者的一种选择 [45]。这些证据表明PI3K/AKT/mTOR通路与CDK4/6抑制剂耐药有关，针对这两个通路的联合策略可能是有效的 [46]。

4. CDK4/6抑制剂的疗效预测生物标志物

由于晚期乳腺癌患者转移病灶活检的困难、潜在风险和患者不适，循环生物标记物在非侵入性识别耐药患者、监测治疗效果和潜在指导后续治疗方面具有巨大潜力。HR阳性和HER-2阴性是目前临床上用于选择CDK4/6抑制剂治疗患者的唯一肿瘤生物标志物。

Rb是CDK4/6的主要磷酸化靶点，磷酸化Rb (Prb)的存在是一个重要的生物标志物。对于Paloma-2和Paloma-3研究的分析表明，Cyclin E/CDK2复合体也可能是有用的生物标志物，在接受CDK4/6抑制剂治疗的患者(来自Paloma-3的队列)中，Cyclin E1 mRNA的高表达与较短的PFS相关，而在之前未治疗的患者(来自Paloma-2的队列)中，Cyclin E1 mRNA的高表达与较短的PFS无关。p16扩增作为生物标志物的作用仍然存在争议，因为对Paloma-1、Paloma-2和Paloma-3的生物标志物分析结果显示，p16/CCND1队列中的PFS与未选择的队列相比没有显著差异 [47] [48] [49]。

正在进行的IIIb期试验Bioitalee (NCT03439046)正在研究ctDNA的改变及其在使用CDK4/6抑制剂和来曲唑作为第一线治疗期间的演变：在参与研究的287名绝经后患者中，有271名患者的样本适合进行初步的生物标志物分析。研究发现，改变最频繁改变的基因是PIK3CA (22.14%)、TP53 (15.50%)、FGFR1 (6.64%)、CDK4 (3.69%)、AKT1 (3.32%)、PTEN (3.32%)、ERBB2 (2.58%)、CCND3 (2.58%)、APC (2.21%)和MAP2K4 (2.21%)。28%的患者出现一种以上基因改变。提示这些生物标志物可能是对CDK4/6抑制剂和来曲唑一线治疗产生内在耐药性的潜在标志。然而，最终的生物标记物动力学和药物基因组学分析仍在进行中。

5. 总结与展望

CDK4/6抑制剂的临床应用代表着HR+/HER-2−乳腺癌治疗的重大进展。这些药物在改善临床结果方面是有效的，但固有或获得性耐药的发展可能会限制这些治疗的疗效。目前，临床研究的重点是研究CDK4/6抑制剂的敏感性或耐药性机制，以及旨在改善临床结果的新的治疗策略。尽管在鉴定CDK4/6抑制剂耐药的潜在基因组驱动因素方面做出了显著而集中的努力，但到目前为止，这些标记都没有显示出临床实用价值。生物标记物前景看好，但需要进一步验证。

文章引用

袁晓莉,王振波. CDK4/6抑制剂在HR+/HER-2−乳腺癌中耐药机制及生物标志物研究进展
Research Progress on Resistance Mechanism and Biomarker of CDK4/6 Inhibitor in HR+/HER-2− Breast Cancer[J]. 临床医学进展, 2021, 11(12): 5754-5761. https://doi.org/10.12677/ACM.2021.1112851

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    50. NOTES

    *通讯作者。

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