Why the study?
Tyrosine kinase inhibitors cause endothelial stress and increase cardiovascular mortality, but the role of translational control in response to this stress remains to be defined.
Does ramipril or SND1 overexpression prevent sunitinib-induced endothelial dysfunction in preclinical models?
Does ramipril or SND1 overexpression prevent sunitinib-induced endothelial dysfunction in preclinical models?
Ramipril and SND1 overexpression protect against sunitinib-induced vascular toxicity in preclinical models, suggesting a potential therapeutic target for TKI-induced cardiovascular side effects.
hiPSC-EC model implicates translational control in TKI vasculopathy; leaves open whether targeting it affects clinical cardiovascular risk.
Translational control shapes the proteome and is particularly important in regulating gene expression under stress. A key source of endothelial stress is treatment with tyrosine kinase inhibitors (TKIs), which lowers cancer mortality but increases cardiovascular mortality. Using a human induced pluripotent stem cell-derived endothelial cell (hiPSC-EC) model of sunitinib-induced vascular dysfunction combined with ribosome profiling, we assessed the role of translational control in hiPSC-ECs in response to stress. We identified staphylococcal nuclease and tudor domain-containing protein 1 (SND1) as a sunitinib-dependent translationally repressed gene. SND1 translational repression was mediated by the mTORC1/4E-BP1 pathway. SND1 inhibition led to endothelial dysfunction, whereas SND1 OE protected against sunitinib-induced endothelial dysfunction. Mechanistically, SND1 transcriptionally regulated UBE2N, an E2-conjugating enzyme that mediates K63-linked ubiquitination. UBE2N along with the E3 ligases RNF8 and RNF168 regulated the DNA damage repair response pathway to mitigate the deleterious effects of sunitinib. In silico analysis of FDA-approved drugs led to the identification of an ACE inhibitor, ramipril, that protected against sunitinib-induced vascular dysfunction in vitro and in vivo, all while preserving the efficacy of cancer therapy. Our study established a central role for translational control of SND1 in sunitinib-induced endothelial dysfunction that could potentially be therapeutically targeted to reduce sunitinib-induced vascular toxicity.
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Han et al. (2025) studied this question.
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