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bioRxiv · 10.1101/2025.08.26.672429

Unbiased CRISPR Synthetic Lethal Screening for Genetic Vulnerabilities in Succinate Dehydrogenase (SDH)-loss Model of Paraganglioma

Al Kazal, F.·Emch, M.·Correia, C.·Favier, J.·Hawse, J.·Maher, L. J.
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Abstract

Succinate dehydrogenase (SDH)-deficient paraganglioma and pheochromocytoma (PPGL) are rare neuroendocrine tumors for which no effective targeted therapies currently exist. To uncover new 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. Notably, several subunits of the transcriptional Mediator complex emerged as potential tumor suppressors, as their loss selectively promoted growth of Sdhb-deficient cells. Most strikingly, we found that the neddylation pathway--required for ubiquitin-mediated selective protein degradation--plays a critical role in controlling cell growth and survival in Sdhb-deficient imCCs. Specifically, loss of the neddylation regulator Ube2m led to increased proliferation, while loss of Ube2f suppressed growth of Sdhb-deficient imCCs. Consequently, global neddylation inhibitor MLN4924 (Pevonedistat) and UBE2F-CRL5 axis inhibitor HA-9104 were shown to downregulate neddylation, suppressing UBE2F activity and selectively inhibiting growth of Sdhb-deficient imCCs. This unexpected result highlights the neddylation pathway as a promising druggable vulnerability in this cell culture model of SDH-deficient PPGL.

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Al Kazal, F., Emch, M., Correia, C., Favier, J., Hawse, J., Maher, L. J.. 2025-08-28. Unbiased CRISPR Synthetic Lethal Screening for Genetic Vulnerabilities in Succinate Dehydrogenase (SDH)-loss Model of Paraganglioma. https://doi.org/10.1101/2025.08.26.672429

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