Unbiased CRISPR synthetic lethal screening for genetic vulnerabilities in a succinate dehydrogenase-loss model of paraganglioma

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.