同行致遠 | 攻克“不可成藥”，精準抗癌療法迎來新篇章 | Bilingual

編者按：近年來，合成致死（synthetic lethality）作為一種獨特的精準治療策略，在抗癌領域得到廣泛關注與應用。目前，已有6款基于該機制的抗癌藥物獲得全球監管機構批準上市，為癌癥患者提供了個體化靶向治療選擇。PARP抑制劑的成功上市，不僅驗證了合成致死策略的臨床潛力，也為探索更多新靶點和藥物打開了大門。長期以來，藥明康德依托其獨特的一體化、端到端CRDMO平臺，持續賦能包括合成致死療法在內的創新藥物研發，助力合作伙伴加速科研成果的轉化落地。本文將介紹藥明康德一體化平臺如何在新藥發現與開發的不同階段推動合成致死藥物的研發。

合成致死的作用機制，是通過利用腫瘤細胞中已存在的遺傳缺陷，在殺傷腫瘤細胞的同時，減少對正常細胞的毒性，為“不可成藥”突變的精準靶向治療提供新思路。其中最具代表性的案例是使用PARP抑制劑治療攜帶

BRCA1/2

▲合成致死作用機制在抗癌藥物開發中的應用（圖片來源：參考資料[6]）

針對合成致死藥物早期開發階段在靶點驗證、機制評估與模型選擇等方面的挑戰，藥明康德旗下的生物學業務平臺（WuXi Biology）可為合作伙伴提供全方位的生物學服務和解決方案，支持從靶點發現到候選藥物篩選再到臨床的各類單體或一體化項目。以針對PARP靶點的新藥開發為例，WuXi Biology可提供一系列體外檢測工具，包括評估PARP1和PARP2結合活性的化學熒光檢測，以及PARP1捕捉（trapping）檢測，支持PARP抑制劑的低通量和高通量化合物篩選，更好地滿足合作伙伴在藥物發現方面的需求。這些檢測方法均已經過獲批PARP抑制劑的驗證。

▲Olaparib的PARP1捕捉檢測實驗結果（圖片來源：參考資料[4]）

在PARP1和PARP2之外，WuXi Biology還可根據客戶的需求定制PARP相關檢測，具備覆蓋其他PARP家族蛋白的能力。已有研究顯示，PARP抑制劑能夠誘導腫瘤細胞內的DNA損傷。WuXi Biology的團隊已經建立DNA損傷相關生物標志物的影像學分析方法，并可配套高內容篩選（HCS）平臺，用于化合物作用機制的深入研究和篩選。

在體內評估方面，WuXi Biology已建立近40種與BRCA缺失相關的動物模型，覆蓋乳腺癌、結直腸癌、胃癌、肺癌、肝癌和胰腺癌等多種癌癥類型，為候選PARP抑制劑的體內研究提供了多樣化工具支持。同時，團隊還構建了模擬PARP抑制劑耐藥性的動物模型，助力合作伙伴深入理解耐藥機制，并探索潛在的應對策略，如組合療法或新一代靶向治療。

PARP之外，PRMT5和WRN也被視為具有前景的新興合成致死靶點。研究顯示，PRMT5抑制劑可選擇性殺傷MTAP缺失的腫瘤細胞，而WRN抑制劑則用于治療具有微衛星不穩定性高（MSI-H）/錯配修復缺陷（dMMR）的實體瘤。針對這兩條合成致死信號通路，WuXi Biology開發了約50款動物模型，涵蓋膀胱癌、乳腺癌、白血病、胃癌、肝癌和黑色素瘤等十余種癌癥類型，為新一代合成致死療法的研發和評估提供有力支持。

上述能力只是WuXi Biology腫瘤學和免疫學團隊的一個縮影。該團隊擁有先進的體外和體內篩選平臺，支持靶點識別和驗證，并建立了完善的免疫腫瘤學轉化平臺，主要包括：

• 生物標志物發現平臺，涵蓋流式細胞術、NanoString、單細胞RNA測序（scRNAseq）、RNAscope以及多重免疫熒光（IF）

• 經過CAP認證的臨床病理學和流式細胞術實驗室，擁有200余個經過臨床驗證的生物標志物，支持臨床藥物開發

• 基于非人靈長類、犬類、豬類的大型動物轉化研究平臺，配套先進設施，具備全面的生物標志物研究和相關性分析能力

合成致死已成為精準治療癌癥的重要策略之一，隨著基礎研究的深入和臨床驗證的持續推進，更多新靶點與新機制有望被發現。藥明康德將繼續依托其獨特的一體化、端到端CRDMO模式，賦能包含合成致死在內的新機制藥物的高效開發，加速將創新成果轉化為惠及全球患者的突破性療法。

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

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.

參考資料：

[1] Synthetic Lethality Related Tumor Models. Retrieved July 23, 2025, from https://wuxibiology.com/wp-content/uploads/2025/03/Synthetic-Lethality-Related-Tumor-Models.pdf

[2] Oncology. Retrieved July 23, 2025, from https://onco.wuxiapptec.com/#/disease?type=57d54d6e26a249a9a08c3cb87470cfa4

[3] Previtali et al., (2024). New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives. J Med Chem., doi:10.1021/acs.jmedchem.4c00113

[4] in vitro PARP Assay. Retrieved July 23, 2025, from https://wuxibiology.com/biology-services/invitro-services/biochemical-assays/in-vitro-parp-assay/

[5] Synthetic Lethality Related Tumor Models. Retrieved July 23, 2025, from https://wuxibiology.com/resource/synthetic-lethality-related-tumor-models/

[6] Ngoi et al., (2024). Synthetic lethal strategies for the development of cancer therapeutics. Nature Reviews Clinical Oncology, https://doi.org/10.1038/s41571-024-00966-z

[7] Peng, et al., (2025). Perspectives on cancer therapy—synthetic lethal precision medicine strategies, molecular mechanisms, therapeutic targets and current technical challenges. Cell Death Discovery, https://doi.org/10.1038/s41420-025-02418-8

[8] Exploring Potential Strategies Overcoming the PARPi Resistance in an Olaparib-Induced MDA-MB-436 Resistant Model. Retrieved July 25, 2025, from https://wuxibiology.com/wp-content/uploads/2025/07/EACR-2025-Poster_Strategies-for-Overcoming-PARP-Inhibitor-Resistance-in-an-Olaparib-Induced-Resistant-Model.pdf

[9] Oncology and Immunology. Retrieved July 25, 2025, from https://wuxibiology.com/biology-services/oncology-immunology/

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