Application of Patient-derived Tumor Organoids in PROTAC Development

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

Abstract

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

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

Figures/Tables 8

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

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

Fig. 2 The timeline of PROTAC technology development

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

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

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

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

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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