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Unbiased CRISPR synthetic lethal screening for genetic vulnerabilities in a succinate dehydrogenase-loss model of
Fatimah J Al Khazal1,2, Michael J Emch1, Cristina Correia3
1Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
Abstract:
Succinate dehydrogenase (SDH)-deficient paraganglioma and pheochromocytoma (PPGL) are rare neuroendocrine neoplasms for which no effective targeted therapies currently exist. To uncover potential therapeutic targets, we performed an unbiased CRISPR-Cas9 genetic screen in immortalized mouse chromaffin cells (imCCs) with and without Sdhb loss. Our screen identified genes that differentially affect cell proliferation in Sdhb-deficient versus normal imCCs. Subunits of the transcriptional mediator complex emerged as potential tumor suppressors, as their loss selectively promoted growth of Sdhb-deficient cells. The neddylation pathway, required for ubiquitin-mediated selective protein degradation, plays a critical role in Sdhb-deficient imCC growth and survival: loss of the neddylation regulator Ube2m led to increased proliferation, while loss of Ube2f suppressed growth of Sdhb-deficient imCCs. Neddylation inhibitors MLN4924 (Pevonedistat) and HA-9104 reduced UBE2F activity and selectively inhibited growth of Sdhb-deficient imCCs. This unexpected result highlights the neddylation pathway as a promising druggable vulnerability to be studied in SDH-deficient PPGL.
Insights
Succinate dehydrogenase (SDH)-deficient paraganglioma and pheochromocytoma (PPGL) are rare tumors lacking targeted therapies. Researchers identified the neddylation pathway as a potential therapeutic target, with inhibitors showing promise in preclinical models.
Area of Science:
- Biochemistry
- Oncology
- Genetics
Background:
- Succinate dehydrogenase (SDH)-deficient paraganglioma and pheochromocytoma (PPGL) are rare neuroendocrine neoplasms.
- Currently, no effective targeted therapies exist for SDH-deficient PPGL.
Purpose of the Study:
- To identify potential therapeutic targets for SDH-deficient PPGL.
- To investigate the role of the neddylation pathway in SDH-deficient PPGL.
Main Methods:
- Unbiased CRISPR-Cas9 genetic screen in immortalized mouse chromaffin cells (imCCs) with and without Sdhb loss.
- Assessed differential gene effects on cell proliferation in Sdhb-deficient vs. normal imCCs.
- Utilized neddylation inhibitors MLN4924 (Pevonedistat) and HA-9104.
Main Results:
- Loss of transcriptional mediator complex subunits selectively promoted growth of Sdhb-deficient cells.
- The neddylation pathway is critical for Sdhb-deficient imCC growth and survival.
- Neddylation inhibitors selectively inhibited growth of Sdhb-deficient imCCs by reducing UBE2F activity.
Conclusions:
- The neddylation pathway represents a druggable vulnerability in SDH-deficient PPGL.
- Neddylation inhibitors show therapeutic potential for treating SDH-deficient PPGL.
- Further study of the neddylation pathway is warranted for SDH-deficient PPGL treatment.
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