Functional genomics pipeline identifies CRL4 inhibition for the treatment of ovarian cancer

IF 6.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Clinical and Translational Medicine Pub Date : 2025-01-24 DOI:10.1002/ctm2.70078

Sally E. Claridge, Shalini Nath, Anneliese Baum, Richard Farias, Julie-Ann Cavallo, Nile M. Rizvi, Lamberto De Boni, Eric Park, Genesis Lara Granados, Matthew Hauesgen, Ruben Fernandez-Rodriguez, Eda Nur Kozan, Evgeny Kanshin, Khoi Q. Huynh, Peng-Jen Chen, Kenneth Wu, Beatrix Ueberheide, Juan Miguel Mosquera, Fred R. Hirsch, Robert J. DeVita, Olivier Elemento, Chantal Pauli, Zhen-Qiang Pan, Benjamin D. Hopkins

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Abstract

Background

The goal of precision oncology is to find effective therapeutics for every patient. Through the inclusion of emerging therapeutics in a high-throughput drug screening platform, our functional genomics pipeline inverts the common paradigm to identify patient populations that are likely to benefit from novel therapeutic strategies.

Approach

Utilizing drug screening data across a panel of 46 cancer cell lines from 11 tumor lineages, we identified an ovarian cancer-specific sensitivity to the first-in-class CRL4 inhibitors KH-4-43 and 33-11. CRL4 (i.e., Cullin-4 RING E3 ubiquitin ligase) is known to be dysregulated in a variety of cancer contexts, making it an attractive therapeutic target. Unlike proteasome inhibitors that are associated with broad toxicity, CRL4 inhibition offers the potential for tumor-specific effects.

Results

We observed that CRL4 inhibition negatively regulates core gene signatures that are upregulated in ovarian tumors and significantly slowed tumor growth as compared to the standard of care, cisplatin, in OVCAR8 xenografts. Building on this, we performed combination drug screening in conjunction with proteomic and transcriptomic profiling to identify ways to improve the antitumor effects of CRL4 inhibition in ovarian cancer models. CRL4 inhibition consistently resulted in activation of the mitogen-activated protein kinase (MAPK) signaling cascade at both the transcriptomic and protein levels, suggesting that survival signaling is induced in response to CRL4 inhibition. These observations were concordant with the results of the combination drug screens in seven ovarian cancer cell lines that showed CRL4 inhibition cooperates with MEK inhibition. Preclinical studies in OVCAR8 and A2780 xenografts confirmed the therapeutic potential of the combination of KH-4-43 and trametinib, which extended overall survival and slowed tumor progression relative to either single agent or the standard of care.

Conclusions

Together, these data demonstrate the prospective utility of functional modeling pipelines for therapeutic development and underscore the clinical potential of CRL4 inhibition in the ovarian cancer context.

Highlights

A precision medicine pipeline identifies ovarian cancer sensitivity to CRL4 inhibitors.
CRL4 inhibition induces activation of MAPK signalling as identified by RNA sequencing, proteomics, and phosphoproteomics.
Inhibitor combinations that target both CRL4 and this CRL4 inhibitor-induced survival signalling enhance ovarian cancer sensitivity to treatment.

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功能基因组学管道确定CRL4抑制卵巢癌的治疗。

背景：精准肿瘤学的目标是为每一位患者找到有效的治疗方法。通过将新兴疗法纳入高通量药物筛选平台，我们的功能基因组学管道颠覆了常见的范式，以确定可能从新型治疗策略中受益的患者群体。方法：利用来自11个肿瘤谱系的46个癌细胞系的药物筛选数据，我们确定了卵巢癌对同类中一流的CRL4抑制剂KH-4-43和33-11的特异性敏感性。众所周知，CRL4（即Cullin-4 RING E3泛素连接酶）在多种癌症环境中失调，使其成为一个有吸引力的治疗靶点。与具有广泛毒性的蛋白酶体抑制剂不同，CRL4抑制具有肿瘤特异性作用的潜力。结果：我们观察到，在OVCAR8异种移植物中，与标准护理顺铂相比，CRL4抑制可负调控卵巢肿瘤中上调的核心基因特征，并显著减缓肿瘤生长。在此基础上，我们结合蛋白质组学和转录组学分析进行了联合药物筛选，以确定在卵巢癌模型中提高CRL4抑制的抗肿瘤作用的方法。CRL4抑制在转录组和蛋白水平上一致导致丝裂原活化蛋白激酶（MAPK）信号级联的激活，表明CRL4抑制诱导了存活信号。这些观察结果与7种卵巢癌细胞系的联合药物筛选结果一致，显示CRL4抑制与MEK抑制协同作用。OVCAR8和A2780异种移植物的临床前研究证实了h -4-43和曲美替尼联合治疗的治疗潜力，相对于单一药物或标准治疗，延长了总生存期，减缓了肿瘤进展。综上所述，这些数据证明了功能建模管道在治疗开发中的潜在效用，并强调了CRL4抑制在卵巢癌中的临床潜力。重点：一项精准药物管线鉴定卵巢癌对CRL4抑制剂的敏感性。通过RNA测序、蛋白质组学和磷酸化蛋白质组学鉴定，CRL4抑制可诱导MAPK信号的激活。同时靶向CRL4和这种CRL4抑制剂诱导的生存信号的抑制剂组合可增强卵巢癌对治疗的敏感性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.