同行致远 | 攻克“不可成药”，精准抗癌疗法迎来新篇章 | Bilingual

（来源：药明康德）

转自：药明康德

编者按：近年来，合成致死（synthetic lethality）作为一种独特的精准治疗策略，在抗癌领域得到广泛关注与应用。目前，已有6款基于该机制的抗癌药物获得全球监管机构批准上市，为癌症患者提供了个体化靶向治疗选择。PARP抑制剂的成功上市，不仅验证了合成致死策略的临床潜力，也为探索更多新靶点和药物打开了大门。长期以来，药明康德依托其独特的一体化、端到端CRDMO平台，持续赋能包括合成致死疗法在内的创新药物研发，助力合作伙伴加速科研成果的转化落地。本文将介绍药明康德一体化平台如何在新药发现与开发的不同阶段推动合成致死药物的研发。

合成致死的作用机制，是通过利用肿瘤细胞中已存在的遗传缺陷，在杀伤肿瘤细胞的同时，减少对正常细胞的毒性，为“不可成药”突变的精准靶向治疗提供新思路。其中最具代表性的案例是使用PARP抑制剂治疗携带BRCA1/2突变的肿瘤。自2014年首款PARP抑制剂olaparib获批以来，niraparib、rucaparib和talazoparib等同类产品也相继问世，并在卵巢癌、乳腺癌、前列腺癌及胰腺癌等适应症中展现出良好疗效与安全性，标志着合成致死从理论研究走向临床应用的重大突破。当前，全球已有超过30种基于合成致死机制的候选药物处于临床开发阶段，其中多数聚焦于DNA损伤修复通路（DDR）、RNA剪接或细胞周期调控等关键机制。除PARP外，WRN、ATR和PRMT等靶点亦成为业内布局的重点方向。

▲合成致死作用机制在抗癌药物开发中的应用（图片来源：参考资料[6]）

针对合成致死药物早期开发阶段在靶点验证、机制评估与模型选择等方面的挑战，药明康德旗下的生物学业务平台（WuXi Biology）可为合作伙伴提供全方位的生物学服务和解决方案，支持从靶点发现到候选药物筛选再到临床的各类单体或一体化项目。以针对PARP靶点的新药开发为例，WuXi Biology可提供一系列体外检测工具，包括评估PARP1和PARP2结合活性的化学荧光检测，以及PARP1捕捉（trapping）检测，支持PARP抑制剂的低通量和高通量化合物筛选，更好地满足合作伙伴在药物发现方面的需求。这些检测方法均已经过获批PARP抑制剂的验证。

▲Olaparib的PARP1捕捉检测实验结果（图片来源：参考资料[4]）

在PARP1和PARP2之外，WuXi Biology还可根据客户的需求定制PARP相关检测，具备覆盖其他PARP家族蛋白的能力。已有研究显示，PARP抑制剂能够诱导肿瘤细胞内的DNA损伤。WuXi Biology的团队已经建立DNA损伤相关生物标志物的影像学分析方法，并可配套高内容筛选（HCS）平台，用于化合物作用机制的深入研究和筛选。

在体内评估方面，WuXi Biology已建立近40种与BRCA缺失相关的动物模型，覆盖乳腺癌、结直肠癌、胃癌、肺癌、肝癌和胰腺癌等多种癌症类型，为候选PARP抑制剂的体内研究提供了多样化工具支持。同时，团队还构建了模拟PARP抑制剂耐药性的动物模型，助力合作伙伴深入理解耐药机制，并探索潜在的应对策略，如组合疗法或新一代靶向治疗。

PARP之外，PRMT5和WRN也被视为具有前景的新兴合成致死靶点。研究显示，PRMT5抑制剂可选择性杀伤MTAP缺失的肿瘤细胞，而WRN抑制剂则用于治疗具有微卫星不稳定性高（MSI-H）/错配修复缺陷（dMMR）的实体瘤。针对这两条合成致死信号通路，WuXi Biology开发了约50款动物模型，涵盖膀胱癌、乳腺癌、白血病、胃癌、肝癌和黑色素瘤等十余种癌症类型，为新一代合成致死疗法的研发和评估提供有力支持。

上述能力只是WuXi Biology肿瘤学和免疫学团队的一个缩影。该团队拥有先进的体外和体内筛选平台，支持靶点识别和验证，并建立了完善的免疫肿瘤学转化平台，主要包括：

• 生物标志物发现平台，涵盖流式细胞术、NanoString、单细胞RNA测序（scRNAseq）、RNAscope以及多重免疫荧光（IF）

• 经过CAP认证的临床病理学和流式细胞术实验室，拥有200余个经过临床验证的生物标志物，支持临床药物开发

• 基于非人灵长类、犬类、猪类的大型动物转化研究平台，配套先进设施，具备全面的生物标志物研究和相关性分析能力

合成致死已成为精准治疗癌症的重要策略之一，随着基础研究的深入和临床验证的持续推进，更多新靶点与新机制有望被发现。药明康德将继续依托其独特的一体化、端到端CRDMO模式，赋能包含合成致死在内的新机制药物的高效开发，加速将创新成果转化为惠及全球患者的突破性疗法。

CRDMO: Tackling the “Undruggable” — Synthetic Lethality Opens A New Chapter for Precision Cancer Therapies

In recent years, synthetic lethality has emerged as a distinctive and promising strategy in precision oncology, attracting growing attention and widespread adoption. To date, six anticancer drugs based on this mechanism have received approval from global regulatory authorities, offering patients individualized targeted therapies. The successful commercialization of PARP inhibitors not only affirms the clinical value of synthetic lethality but also opens new avenues for the exploration of additional therapeutic targets and modalities.

Leveraging its unique, fully integrated, end-to-end CRDMO (Contract Research, Development and Manufacturing Organization) platform, WuXi AppTec has supported the development of innovative oncology therapies—including those based on synthetic lethality—helping partners accelerate the translation of scientific discoveries into impactful treatments. This article explores how WuXi AppTec’s platform enables synthetic lethality drug development at every stage, from early discovery to clinical advancement.

At its core, synthetic lethality exploits existing genetic vulnerabilities within tumor cells, allowing for the selective killing of cancer cells while sparing normal tissue. This mechanism also offers a promising route to target mutations that were once considered “undruggable.” A well-established application of this concept is the use of PARP inhibitors in patients with BRCA1/2-mutated tumors. Since the approval of the first PARP inhibitor, olaparib, in 2014, additional agents such as niraparib, rucaparib, and talazoparib have entered the market. These therapies have demonstrated favorable efficacy and safety profiles across several indications, including ovarian, breast, prostate, and pancreatic cancers, representing a major leap in bringing synthetic lethality from bench to bedside.

Globally, more than 30 drug candidates based on synthetic lethality are currently in clinical development. Most of these focus on core biological mechanisms such as DNA damage repair (DDR), RNA splicing, and cell cycle regulation. In addition to PARP, targets such as WRN, ATR, and PRMT have garnered significant industry interest, driving further innovation and investment in this space.

To address early-stage challenges in synthetic lethality drug development, such as target discovery, mechanism validation, and selecting appropriate models, WuXi Biology provides comprehensive biological services and solutions. These capabilities support both stand-alone and fully integrated projects, ranging from target discovery to candidate screening and clinical progression.

For example, in the development of new PARP-targeted therapies, WuXi Biology offers a broad suite of in vitro assay tools, including chemiluminescent assays to assess PARP1 and PARP2 binding activity, as well as PARP1 trapping assays. These tools enable both low- and high-throughput compound screening, helping partners meet diverse drug discovery needs. All assays have been validated with approved PARP inhibitors.

Beyond PARP1 and PARP2, WuXi Biology has the capability to set up experiments for other PARP proteins, and PARP-related assays can be customized according to clients’ needs. Research has shown that long-term incubation with PARP inhibitors can induce DNA damage within tumor cells. To support such investigations, WuXi Biology has developed imaging-based analysis platforms for DNA damage-related biomarkers, compatible with high-content screening (HCS) to facilitate deeper understanding of compound mechanisms of action.

In vivo, WuXi Biology has established about 40 animal models associated with BRCA deficiency. These models cover a wide range of cancer types, including breast, colorectal, gastric, lung, liver, and pancreatic cancers, providing flexible tools for evaluating PARP inhibitor candidates. Additionally, the team has developed models that simulate resistance to PARP inhibitors, enabling partners to explore resistance mechanisms and evaluate strategies to overcome them—such as combination therapies or next-generation targeted agents.

Emerging synthetic lethality targets such as PRMT5 and WRN are also gaining momentum. PRMT5 inhibitors have demonstrated selective cytotoxicity in tumors with MTAP deletions, while WRN inhibitors are being investigated for use in tumors characterized by high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR). To support drug development targeting these pathways, WuXi Biology has built approximately 50 animal models spanning more than a dozen tumor types, including bladder cancer, breast cancer, leukemia, gastric cancer, liver cancer, and melanoma.

The capabilities outlined above are just a glimpse into the expertise of WuXi Biology’s oncology and immunology teams. The team offers advanced in vitro and in vivo screening platforms for target identification and validation and has also built a robust immuno-oncology translational platform that includes:

• A biomarker discovery platform featuring flow cytometry, NanoString, single-cell RNA sequencing (scRNAseq), RNAscope, and multiplex immunofluorescence (IF)

• CAP certified lab for clinical pathology and flow cytometry with over 200 clinically validated biomarkers to support clinical drug development

• Large animal (NHP, canine, swine) based translational research platform with state-of-the-art facilities, comprehensive biomarker research and correlation capability

Synthetic lethality has become one of the most impactful strategies in precision oncology. With continuous progress in fundamental research and clinical validation, new targets and mechanisms will continue to emerge. WuXi AppTec remains committed to leveraging its integrated, end-to-end CRDMO platform to accelerate the development of novel therapies—including those grounded in synthetic lethality—and to help transform scientific innovation into breakthrough treatments that improve lives worldwide.

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