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

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

  • Clin Transl Med. 2025 Feb;15(2):e70078. doi: 10.1002/ctm2.70078.
Sally E Claridge 1 2 3 4 5,  Shalini Nath 1 2,  Anneliese Baum 3 4,  Richard Farias 3 4,  Julie-Ann Cavallo 3 4,  Nile M Rizvi 3 4,  Lamberto De Boni 1 2 3 4 5,  Eric Park 3 4,  Genesis Lara Granados 3 4,  Matthew Hauesgen 3 4,  Ruben Fernandez-Rodriguez 4 5,  Eda Nur Kozan 2 6,  Evgeny Kanshin 7 8,  Khoi Q Huynh 9 10,  Peng-Jen Chen 9 10,  Kenneth Wu 4,  Beatrix Ueberheide 7 8 11,  Juan Miguel Mosquera 2 6,  Fred R Hirsch 5 12 13,  Robert J DeVita 8 9,  Olivier Elemento 2 14 15,  Chantal Pauli 16,  Zhen-Qiang Pan 3,  Benjamin D Hopkins 1 2
Affiliations

Affiliations

  • 1 Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York, USA.
  • 2 Englander Institute for Precision Medicine, Weill Cornell Medicine, New York Presbyterian Hospital, New York, New York, USA.
  • 3 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 4 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 5 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 6 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA.
  • 7 Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA.
  • 8 Proteomics Laboratory, New York University School of Medicine, New York, New York, USA.
  • 9 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 10 Drug Discovery Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 11 Department of Neurology, New York University Grossman School of Medicine, New York, New York, USA.
  • 12 Department of Medicine, Hematology, and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 13 Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 14 Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York, USA.
  • 15 Clinical and Translational Science Center, Weill Cornell Medicine, New York, New York, USA.
  • 16 Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.
PMID: 39856363 DOI: 10.1002/ctm2.70078
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.

Keywords

CRL4; functional genomics; ovarian cancer; precision oncology.

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