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Published on: January 12, 2020
Functional genomics pipeline identifies CRL4 inhibition for the treatment of ovarian cancer
Sally E Claridge1,2,3,4,5, Shalini Nath1,2, Anneliese Baum3,4
1Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York, USA.
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.
Insights
Precision oncology identified ovarian cancer sensitivity to CRL4 inhibitors. Combining CRL4 inhibition with MEK inhibition shows promise for treating ovarian cancer by overcoming induced survival signaling.
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- Precision oncology aims to tailor effective treatments for individual patients.
- A functional genomics pipeline identifies patient populations likely to benefit from novel therapeutics.
- Emerging therapeutics are integrated into high-throughput drug screening platforms.
Purpose of the Study:
- To identify patient populations responsive to novel therapeutic strategies.
- To investigate the efficacy of CRL4 inhibitors in ovarian cancer.
- To explore combination therapies to enhance treatment outcomes.
Main Methods:
- High-throughput drug screening across 46 cancer cell lines from 11 tumor lineages.
- Utilized CRL4 inhibitors (KH-4-43, 33-11) and MEK inhibitors (trametinib).
- Performed proteomic and transcriptomic profiling, including RNA sequencing and phosphoproteomics.
Main Results:
- Ovarian cancer cell lines exhibited specific sensitivity to CRL4 inhibitors.
- CRL4 inhibition slowed tumor growth in xenografts and regulated core gene signatures.
- Combination therapy with CRL4 and MEK inhibitors demonstrated enhanced antitumor effects and extended survival in preclinical models.
- CRL4 inhibition activated the MAPK signaling cascade, indicating induced survival signaling.
Conclusions:
- Functional modeling pipelines are valuable for therapeutic development in precision oncology.
- CRL4 inhibition presents significant clinical potential for ovarian cancer treatment.
- Targeting both CRL4 and the induced MAPK survival pathway enhances treatment efficacy in ovarian cancer.
