Englander Institute for Precision Medicine

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

TitleFunctional genomics pipeline identifies CRL4 inhibition for the treatment of ovarian cancer.
Publication TypeJournal Article
Year of Publication2025
AuthorsClaridge SE, Nath S, Baum A, Farias R, Cavallo J-A, Rizvi NM, De Boni L, Park E, Granados GLara, Hauesgen M, Fernandez-Rodriguez R, Kozan ENur, Kanshin E, Huynh KQ, Chen P-J, Wu K, Ueberheide B, Mosquera JMiguel, Hirsch FR, DeVita RJ, Elemento O, Pauli C, Pan Z-Q, Hopkins BD
JournalClin Transl Med
Volume15
Issue2
Paginatione70078
Date Published2025 Feb
ISSN2001-1326
KeywordsAnimals, Antineoplastic Agents, Cell Line, Tumor, Female, Genomics, Humans, Mice, Ovarian Neoplasms
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.

DOI10.1002/ctm2.70078
Alternate JournalClin Transl Med
PubMed ID39856363
PubMed Central IDPMC11761363
Grant ListR00 CA230384 / CA / NCI NIH HHS / United States
K99 CA230384 / CA / NCI NIH HHS / United States
CA230384-03 / / National Cancer Institute of the National Institutes of Health /
CA251425 / / National Cancer Institute of the National Institutes of Health /
R01 CA251425 / CA / NCI NIH HHS / United States
T32 CA078207 / CA / NCI NIH HHS / United States
5T32CA078207-22 / / National Cancer Institute of the National Institutes of Health /

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