患者来源肿瘤类器官在PROTAC开发中的应用

doi:10.13560/j.cnki.biotech.bull.1985.2026-0330

摘要/Abstract

摘要：

蛋白水解靶向嵌合体（proteolysis targeting chimeras, PROTAC）技术作为新一代靶向蛋白降解技术，利用细胞内的泛素-蛋白酶体系统（ubiquitin-proteasome system, UPS）特异性降解靶蛋白，现已成为抗肿瘤药物研发的核心热点，但该技术的临床转化仍受传统体外模型与临床实际疗效脱节的严重限制。患者来源肿瘤类器官（patient-derived tumor organoid, PDTO）可高度还原肿瘤的基因组及表观遗传特征、组织学结构、瘤内异质性，有望推动抗肿瘤药物的临床转化进程。PROTAC技术与PDTO的交叉融合已成为创新药物研发的新兴研究方向，在PROTAC个体化筛选与评价、耐药性克服、靶向“不可成药”靶点等方面都展现出极大的应用潜力。本文对PDTO在PROTAC开发中的研究现状进行梳理，分析这一交叉融合领域研究的优势、面临的挑战，以及可能的改进方向，旨在为PROTAC技术的临床转化与患者来源肿瘤类器官模型的应用拓展提供参考。

关键词: PROTAC技术, 患者来源肿瘤类器官, 交叉融合, 个体化筛选, 耐药性, 不可成药靶点

Abstract:

Proteolysis-targeting chimeras (PROTACs) represent a new generation of targeted protein degradation technology that harnesses the intracellular ubiquitin-proteasome system (UPS) to specifically degrade target proteins, and have become a central focus in anticancer drug development. However, the clinical translation of this technology remains severely limited by the discrepancy between results from traditional in vitro models and actual clinical efficacy. Patient-derived tumor organoid (PDTO) can faithfully recapitulate the genomic and epigenetic characteristics, histological architecture, and intratumoral heterogeneity of tumors, thereby offering great promise for advancing the clinical translation of anticancer drugs. The integration of PROTAC technology with PDTO has emerged as a promising direction in innovative drug development. This approach holds significant potential for applications such as personalized PROTAC screening and evaluation, overcoming drug resistance, and targeting previously undruggable targets. This article reviews the current state of research on PDTO in PROTAC development, analyzes the advantages and challenges in this interdisciplinary field, and discusses future directions for improvement, aiming to provide guidance for the clinical translation of PROTAC technology and the broader application of patient-derived tumor organoid models.

Key words: PROTAC technology, patient-derived tumor organoids, interdisciplinary integration, personalized screening, drug resistance, undruggable targets

刘亚琪, 李瑶宣, 刘含霄, 李孟娜, 杨竞超, 陈兵, 杨凤堂, 李敬瑞. 患者来源肿瘤类器官在PROTAC开发中的应用[J]. 生物技术通报, 2026, 42(11): 70-80.

LIU Ya-qi, LI Yao-xuan, LIU Han-xiao, LI Meng-na, YANG Jing-chao, CHEN Bing, YANG Feng-tang, LI Jing-rui. Application of Patient-derived Tumor Organoids in PROTAC Development[J]. Biotechnology Bulletin, 2026, 42(11): 70-80.

图/表 8

表1 PROTAC与其他肿瘤治疗方法比较

Table 1 Comparison of PROTAC with other therapeutic modalities

比较维度 Comparison dimensions	蛋白水解靶向嵌合体 PROTAC	小分子化合物 Small molecule	基因编辑技术 CRISPR	单克隆抗体 Monoclonal antibody	小干扰RNA siRNA
作用于胞内靶点 Intracellular targets	Yes	Yes	Yes	No	Yes
全身给药 Systemic delivery	Yes	Yes	No	Yes	Yes
循环催化作用机制 Cyclic catalytic mode of action	Yes	No	No	No	No
口服生物利用度 Oral bioavailability	Yes	Yes	No	No	No
无可成药靶点限制 No druggable target constraint	Yes	No	Yes	No	Yes
肿瘤类器官适配性 Tumor organoid compatibility	Yes	Yes	Yes	No	Yes

图1 PROTAC工作原理示意图（借助Figdraw自主绘制，下同）图中展示了PROTAC利用细胞内泛素-蛋白酶体系统，特异性催化降解靶蛋白的完整循环过程。POI：靶蛋白；PROTAC：蛋白水解靶向嵌合体；E3：E3泛素连接酶；E2：E2泛素结合酶；Ub：泛素；Proteasome：26S蛋白酶体。橙色箭头指示反应正向流程；蓝色箭头指示PROTAC分子可从复合物中释放并循环参与下一轮降解反应

Fig. 1 Schematic diagram of PROTAC working principle (self-drawn by Figdraw, the same below)This figure illustrates the complete cycle of how PROTACs utilize the intracellular ubiquitin-proteasome system to specifically catalyze the degradation of target proteins. POI: Target protein. PROTAC: proteolysis targeting chimera. E3: E3 ubiquitin ligase. E2: E2 ubiquitin-conjugating enzyme. Ub: Ubiquitin. Proteasome: 26S proteasome. Orange arrows indicate the forward reaction flow; blue arrows indicate that the PROTAC molecule can be released from the complex and recycled for the next round of degradation

图2 PROTAC技术发展历程

Fig. 2 The timeline of PROTAC technology development

图3 患者来源肿瘤类器官的构建流程示意图

Fig. 3 Schematic diagram of patient-derived tumor organoid construction process

表2 患者来源肿瘤类器官与2D细胞系、动物模型的比较

Table 2 Comparison of patient-derived tumor organoids with 2D cell lines and animal models

比较维度 Comparison dimensions	患者来源肿瘤类器官 Patient-derived tumor organoids	二维细胞系 2D cell lines	动物模型 Animal models
生理相关性 Physiological relevance	High	Low	High
肿瘤异质性 Tumor heterogeneity	High	Low	High
三维结构 3D structure	Present	Absent	Present
构建周期 Build cycle	Moderate	Short	Long
通量 Throughput	Moderate	High	Low
个体化治疗 Personalized therapy	High	Low	Low
成本 Cost	Moderate	Low	High

图4 基于患者来源肿瘤类器官的PROTAC开发全流程示意图图中展示了以PROTAC和PDTO为核心的研究体系，涵盖患者肿瘤组织采集、肿瘤类器官生物样本库建立、PROTAC高通量筛选、药效与耐药性评估及个体化临床治疗

Fig. 4 Schematic diagram of the entire workflow for PROTAC development based on patient-derived tumor organoidsThis figure illustrates the research system centered on PROTAC and PDTO, covering the collection of patient tumor tissues, the establishment of a tumor organoid biobank, high-throughput PROTAC screening, evaluation of drug efficacy and resistance, and personalized clinical treatment

图5 基于乳腺癌类器官的PI3K PROTAC克服拉帕替尼耐药A：PI3K-p110α蛋白持续激活导致的拉帕替尼耐药；B：PI3K PROTAC降解突变的p110α蛋白，阻断PI3K/AKT信号级联，逆转耐药

Fig. 5 PI3K PROTAC overcomes lapatinib resistance in breast cancer organoidsA: Lapatinib resistance caused by sustained activation of the PI3K-p110α protein. B: PI3K PROTAC degrades the mutated p110α protein, blocking the PI3K/AKT signaling cascade and ultimately reversing resistance

图6 FER介导的促癌信号通路及基于PDTO的PROTAC抑制A：FER高表达通过双重调控机制持续激活MAPK通路并入核诱导相关基因转录，驱动肿瘤恶性进展；B：PROTAC降解剂靶向降解FER，逆转肿瘤侵袭与转移等恶性表型

Fig. 6 FER-mediated oncogenic signaling pathways and PDTO-based PROTAC inhibitionA: High FER expression continuously activates the MAPK pathway through a dual regulatory mechanism and induces the transcription of related genes upon nuclear translocation, driving malignant tumor progression. B: PROTAC-based degraders specifically degrade FER, thereby reversing malignant phenotypes such as tumor invasion and metastasis

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