Pandit, Shusil K Sandrini, Giada Merulla, Jessica Nobili, Valentina Wang, Xin Zangari, Alessia Rinaldi, Andrea Shinde, Dheeraj Carbone, Giuseppina M. Catapano, Carlo V. 2021 The multi-kinase inhibitor sorafenib is a primary treatment modality for advanced-stagehepatocellular carcinoma (HCC). However, the therapeutic benefits are short-lived due to innateand acquired resistance. Here, we examined how HCC cells respond to sorafenib and adapt tocontinuous and prolonged exposure to the drug. Sorafenib-adapted HCC cells show a profoundreprogramming of mitochondria function and marked activation of genes required for mitochondrialprotein translation and biogenesis. Mitochondrial ribosomal proteins and components of translationand import machinery are increased in sorafenib-resistant cells and sorafenib-refractory HCC patientsshow similar alterations. Sorafenib-adapted cells also exhibited increased serine 727 phosphorylated(pSer727) STAT3, the prevalent form in mitochondria, suggesting that STAT3 might be an actionabletarget to counteract resistance. Consistently, a small-molecule STAT3 inhibitor reduces pSer727,reverts mitochondrial alterations, and enhances the response to sorafenib in resistant cells. Theseresults sustain the importance of mitochondria plasticity in response to sorafenib and identify aclinically actionable strategy for improving the treatment efficacy in HCC patients. application/pdf https://susi.usi.ch/global/documents/321226 https://localhost:5000/ark:/12658/srd1321226 https://susi.usi.ch/documents/321226/files/Catapano_2021_MDPI_cancers.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.3390/cancers13236029 info:eu-repo/semantics/altIdentifier/ark/12658/srd1321226 info:eu-repo/semantics/openAccess CC BY Cancers. - 2021, vol. 13, no. 23, p. 6029 Liver cancer Hepatocellular carcinoma Sorafenib Tyrosine kinase inhibitors Drug resistance Mitochondria Mitochondrial protein translation Mitochondrial ribosomal proteins STAT3 OPB-111077 info:eu-repo/classification/udc/61 Mitochondrial plasticity promotes resistance to sorafenib and vulnerability to STAT3 inhibition in human hepatocellular carcinoma http://purl.org/coar/resource_type/c_6501