Statins inhibit onco-dimerization of the 4Ig isoform of B7-H3

Sutton, M. N.; Glazer, S. E.; Al Zaki, A.; Napoli, A.; Yang, P.; Bhosale, P.; Liu, J.; Gammon, S. T.; Piwnica-Worms, D.

doi:10.1101/2024.12.18.628944

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bioRxiv · 10.1101/2024.12.18.628944

Statins inhibit onco-dimerization of the 4Ig isoform of B7-H3

Sutton, M. N.·Glazer, S. E.·Al Zaki, A.·Napoli, A.·Yang, P.·Bhosale, P.·Liu, J.·Gammon, S. T.·Piwnica-Worms, D.

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Abstract

B7-H3 (CD276), a member of the B7-family of immune checkpoint proteins, has been shown to have immunological and non-immunological effects promoting tumorigenesis [1, 2] and expression correlates with poor prognosis for many solid tumors, including cervical, ovarian and breast cancers [3-6]. We recently identified a tumor-cell autochthonous tumorigenic role for dimerization of the 4Ig isoform of B7-H3 (4Ig-B7-H3) [7], where 4Ig-B7-H3 dimerization in cis activated tumor-intrinsic cellular proliferation and tumorigenesis pathways, providing a novel opportunity for therapeutic intervention. Herein, a live cell split-luciferase complementation strategy was used to visualize 4Ig-B7-H3 homodimerization in a high-throughput small molecule screen (HTS) to identify modulators of this protein-protein interaction (PPI). Notably, the HTS identified several compounds that converged on lipid metabolism (including HMG-CoA reductase inhibitors, also known as statins) as significant inhibitors of 4Ig-B7-H3 dimerization (p < 0.01). In vitro and in vivo murine studies provided evidence that statin-mediated disruption of 4Ig-B7-H3 dimerization was associated with anti-tumor effects. Statin-mediated anti-cancer efficacy was selective for B7-H3-expressing tumors and retrospective analysis of clinical tumor specimens supported the hypothesis that concurrent statin use enhanced clinical outcomes for patients in a B7-H3 restricted manner. Thus, disruption of 4Ig-B7-H3 dimerization provides an unanticipated molecular mechanism linking statin use in cancer therapy and prevention with immune checkpoint.

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Sutton, M. N., Glazer, S. E., Al Zaki, A., Napoli, A., Yang, P., Bhosale, P., Liu, J., Gammon, S. T., Piwnica-Worms, D.. 2024-12-20. Statins inhibit onco-dimerization of the 4Ig isoform of B7-H3. https://doi.org/10.1101/2024.12.18.628944

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