Loss-of-SIRT7 sensitizes hepatocellular carcinoma to sorafenib through the regulation of ERK Phosphorylation

Kim, Y.; Jung, K.-Y.; Kim, Y. H.; Xu, P.; Jo, Y.; Kang, B. E.; Pandit, N.; Kwon, J.; Gariani, K.; Gariani, J.; Lee, J.; Verbeek, J.; Nam, S.; Bae, S.-J.; Ha, K.-T.; Yi, H.-S.; Shong, M.; Kim, K.-H.; Kim, D.; Lee, C.-W.; Jung, H. J.; Kim, K. R.; Schoonjans, K.; Ryu, D.; Auwerx, J.

doi:10.1101/2023.03.13.531998

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bioRxiv · 10.1101/2023.03.13.531998

Loss-of-SIRT7 sensitizes hepatocellular carcinoma to sorafenib through the regulation of ERK Phosphorylation

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Abstract

The FDA-approved oral multi-kinase inhibitor, sorafenib (BAY 43-9006, Nexavar), is the first approved systemic therapy for patients with unresectable hepatocellular carcinoma (HCC). Although it has been shown to significantly improve the overall survival of patients with HCC, drug resistance limits the response rate to this therapeutic. Here, we report that acquired sorafenib resistance is associated with overexpression of the deacetylase, SIRT7, and a high level of ERK phosphorylation. Further, we identify that the hyperactivation of ERK is controlled by SIRT7-mediated deacetylation of DDX3X. The inhibition of SIRT7 combined with sorafenib resulted in a marked reduction of cell viability in vitro and of tumor growth in vivo. It seems plausible that SIRT7 is responsible for the acquired sorafenib resistance and its inhibition is most likely beneficial together in conjunction with sorafenib by suppressing ERK signaling. HighlightsO_LISorafenib resistance in HCC is associated with SIRT7 and ERK hyperactivation. C_LIO_LISuppression of SIRT7 combined with sorafenib restores sensitivity to sorafenib. C_LIO_LISIRT7 controls sorafenib resistance through ERK activation by mediating DDX3X deacetylation. C_LI

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Kim, Y., Jung, K.-Y., Kim, Y. H., Xu, P., Jo, Y., Kang, B. E., Pandit, N., Kwon, J., Gariani, K., Gariani, J., Lee, J., Verbeek, J., Nam, S., Bae, S.-J., Ha, K.-T., Yi, H.-S., Shong, M., Kim, K.-H., Kim, D., Lee, C.-W., Jung, H. J., Kim, K. R., Schoonjans, K., Ryu, D., Auwerx, J.. 2023-03-15. Loss-of-SIRT7 sensitizes hepatocellular carcinoma to sorafenib through the regulation of ERK Phosphorylation. https://doi.org/10.1101/2023.03.13.531998

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