{"doi":"10.1016/j.jcmgh.2020.03.007","title":"Incapacitated Capicua in Sorafenib-Resistant HCC","abstract":"Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality. A majority of patients with HCC present at advanced stages, and are ineligible for potentially curative treatments such as liver transplantation or resection. Sorafenib is a multikinase inhibitor that has long been used as a first-line treatment for advanced unresectable HCC. Although it moderately improves median survival, primary or acquired sorafenib resistance occurs and HCC ultimately progresses.1Zhu Y. Zheng B. Wang H. Chen L. New knowledge of the mechanisms of sorafenib resistance in liver cancer.Acta Pharmacol Sin. 2017; 38: 614-622Crossref PubMed Scopus (322) Google Scholar A better understanding of resistance mechanisms may lead to improved treatment approaches such as combination drug therapies or molecular-guided therapy. High-throughput sequencing technologies have helped to identify primary resistance mechanisms such as alterations in mitogen-activated protein kinase 14 and vascular endothelial growth factor A,1Zhu Y. Zheng B. Wang H. Chen L. New knowledge of the mechanisms of sorafenib resistance in liver cancer.Acta Pharmacol Sin. 2017; 38: 614-622Crossref PubMed Scopus (322) Google Scholar,2Rudalska R. Dauch D. Longerich T. McJunkin K. Wuestefeld T. Kang T.-W. Hohmeyer A. Pesic M. Leibold J. von Thun A. Schirmacher P. Zuber J. Weiss K.-H. Powers S. Malek N.P. Eilers M. Sipos B. Lowe S.W. Geffers R. Laufer S. Zender L. In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer.Nat Med. 2014; 20: 1138-1146Crossref PubMed Scopus (201) Google Scholar but acquired resistance from the clonal selection of cells with mutations has not been examined in patients. In this issue of Cellular and Molecular Gastroenterology and Hepatology, Hashiba et al3Hashiba T. Yamashita T. Okada H. Nio K. Hayashi T. Asahina Y. Hayashi T. Terashima T. Iida N. Taketori H. Shimakami T. Kawaguchi K. Arai K. Sakai Y. Yamashita T. Mizukoshi E. Takamura H. Ohta T. Honda M. Kaneko S. Inactivation of transcriptional repressor Capicua confers sorafenib resistance in human hepatocellular carcinoma.Cell Mol Gastroenterol and Hepatol. 2020; 10: 269-285Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar provide a proof-of-concept study of discovery of acquired sorafenib resistance resulting from a mutation in capicua transcriptional repressor (CIC), by examining tissues from a patient who developed recurrent HCC while on sorafenib. This patient was part of the Sorafenib as Adjuvant Treatment in the Prevention Of Recurrence of Hepatocellular Carcinoma (STORM) trial, which evaluated the benefit of sorafenib as an adjuvant treatment in patients at the highest risk of developing HCC.4Bruix J. Takayama T. Mazzaferro V. Chau G.-Y. Yang J. Kudo M. Cai J. Poon R.T. Han K.-H. Tak W.Y. Lee H.C. Song T. Roayaie S. Bolondi L. Lee K.S. Makuuchi M. Souza F. Le Berre M.-A. Meinhardt G. Llovet J.M. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial.Lancet Oncol. 2015; 16: 1344-1354Abstract Full Text Full Text PDF PubMed Scopus (565) Google Scholar Although this was a negative study, secondary analysis has identified a molecular signature that can predict response to sorafenib.5Pinyol R. Montal R. Bassaganyas L. Sia D. Takayama T. Chau G.-Y. Mazzaferro V. Roayaie S. Lee H.C. Kokudo N. Zhang Z. Torrecilla S. Moeini A. Rodriguez-Carunchio L. Gane E. Verslype C. Croitoru A.E. Cillo U. de la Mata M. Lupo Strasser S. Park J.-W. Camps J. Solé Manel Thung S.N. Villanueva A. Pena C. Meinhardt G. Bruix J. Llovet J.M. Molecular predictors of prevention of recurrence in HCC with sorafenib as adjuvant treatment and prognostic factors in the phase 3 STORM trial.Gut. 2019; 68: 1065-1075Crossref PubMed Scopus (105) Google Scholar The patient described by Hashiba et al3Hashiba T. Yamashita T. Okada H. Nio K. Hayashi T. Asahina Y. Hayashi T. Terashima T. Iida N. 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