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

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 loss. Our screen identified genes that differentially affect cell proliferation in -deficient versus normal imCCs. Notably, several subunits of the transcriptional Mediator complex emerged as potential tumor suppressors, as their loss selectively promoted growth of -deficient cells. , we found that the neddylation pathway-required for ubiquitin-mediated selective protein degradation-plays a critical role in controlling cell growth and survival in -deficient imCCs. Specifically, loss of the neddylation regulator led to increased proliferation, while loss of suppressed growth of -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 -deficient imCCs. This unexpected result highlights the neddylation pathway as a promising druggable vulnerability in this cell culture model of SDH-deficient PPGL.