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Article: Efficacy of annexin A3 blockade in sensitizing hepatocellular carcinoma to sorafenib and regorafenib

TitleEfficacy of annexin A3 blockade in sensitizing hepatocellular carcinoma to sorafenib and regorafenib
Authors
KeywordsSorafenib resistance
Regorafenib
Liver cancer
ANXA3
Antibody therapy
Issue Date2018
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jhep
Citation
Journal of Hepatology, 2018, v. 69 n. 4, p. 826-839 How to Cite?
AbstractBackground & Aims: Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Sorafenib is the only FDA-approved first-line targeted drug for advanced HCC, but its effect on patient survival is limited. Further, patients ultimately present with disease progression. A better understanding of the causes of sorafenib resistance, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucial to achieve efficient control of HCC. Methods: The functional effects of ANXA3 in conferring sorafenib resistance to HCC cells were analyzed in apoptotic and tumorigenicity assays. The role of ANXA3/PKCδ-mediated p38 signaling, and subsequently altered autophagic and apoptotic events, was assessed by immunoprecipitation, immunoblotting, immunofluorescence and transmission electron microscopy assays. The prognostic value of ANXA3 in predicting response to sorafenib was evaluated by immunohistochemistry. The therapeutic value of targeting ANXA3 to combat HCC with anti-ANXA3 monoclonal antibody alone or in combination with sorafenib/regorafenib was investigated ex vivo and in vivo. Results: ANXA3 conferred HCC cells with resistance to sorafenib. ANXA3 was found enriched in sorafenib-resistant HCC cells and patient-derived xenografts. Mechanistically, overexpression of ANXA3 in sorafenib-resistant HCC cells suppressed PKCδ/p38 associated apoptosis and activated autophagy for cell survival. Clinically, ANXA3 expression correlated positively with the autophagic marker LC3B in HCC and was associated with a worse overall survival in patients who went on to receive sorafenib treatment. Anti-ANXA3 monoclonal antibody therapy combined with sorafenib/regorafenib impaired tumor growth in vivo and significantly increased survival. Conclusion: Anti-ANXA3 therapy in combination with sorafenib/regorafenib represents a novel therapeutic strategy for HCC treatment. ANXA3 represents a useful predictive biomarker to stratify patients with HCC for sorafenib treatment. Lay summary: This study represents the most extensive pre-clinical characterization of anti-ANXA3 monoclonal antibodies for the treatment of hepatocellular carcinoma to date. These results support the clinical trial development of anti-ANXA3 antibodies in combination with sorafenib/regorafenib. Further studies will optimize patient target selection and identify the best treatment combinations.
Persistent Identifierhttp://hdl.handle.net/10722/259068
ISSN
2023 Impact Factor: 26.8
2023 SCImago Journal Rankings: 9.857
ISI Accession Number ID
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DC FieldValueLanguage
dc.contributor.authorTong, M-
dc.contributor.authorChe, N-
dc.contributor.authorZhou, L-
dc.contributor.authorLuk, ST-
dc.contributor.authorLui Kau, WF-
dc.contributor.authorChai, S-
dc.contributor.authorNgan, ES-
dc.contributor.authorLo, CM-
dc.contributor.authorMan, K-
dc.contributor.authorDing, J-
dc.contributor.authorLee, TK-
dc.contributor.authorMa, SKY-
dc.date.accessioned2018-09-03T04:01:01Z-
dc.date.available2018-09-03T04:01:01Z-
dc.date.issued2018-
dc.identifier.citationJournal of Hepatology, 2018, v. 69 n. 4, p. 826-839-
dc.identifier.issn0168-8278-
dc.identifier.urihttp://hdl.handle.net/10722/259068-
dc.description.abstractBackground & Aims: Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Sorafenib is the only FDA-approved first-line targeted drug for advanced HCC, but its effect on patient survival is limited. Further, patients ultimately present with disease progression. A better understanding of the causes of sorafenib resistance, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucial to achieve efficient control of HCC. Methods: The functional effects of ANXA3 in conferring sorafenib resistance to HCC cells were analyzed in apoptotic and tumorigenicity assays. The role of ANXA3/PKCδ-mediated p38 signaling, and subsequently altered autophagic and apoptotic events, was assessed by immunoprecipitation, immunoblotting, immunofluorescence and transmission electron microscopy assays. The prognostic value of ANXA3 in predicting response to sorafenib was evaluated by immunohistochemistry. The therapeutic value of targeting ANXA3 to combat HCC with anti-ANXA3 monoclonal antibody alone or in combination with sorafenib/regorafenib was investigated ex vivo and in vivo. Results: ANXA3 conferred HCC cells with resistance to sorafenib. ANXA3 was found enriched in sorafenib-resistant HCC cells and patient-derived xenografts. Mechanistically, overexpression of ANXA3 in sorafenib-resistant HCC cells suppressed PKCδ/p38 associated apoptosis and activated autophagy for cell survival. Clinically, ANXA3 expression correlated positively with the autophagic marker LC3B in HCC and was associated with a worse overall survival in patients who went on to receive sorafenib treatment. Anti-ANXA3 monoclonal antibody therapy combined with sorafenib/regorafenib impaired tumor growth in vivo and significantly increased survival. Conclusion: Anti-ANXA3 therapy in combination with sorafenib/regorafenib represents a novel therapeutic strategy for HCC treatment. ANXA3 represents a useful predictive biomarker to stratify patients with HCC for sorafenib treatment. Lay summary: This study represents the most extensive pre-clinical characterization of anti-ANXA3 monoclonal antibodies for the treatment of hepatocellular carcinoma to date. These results support the clinical trial development of anti-ANXA3 antibodies in combination with sorafenib/regorafenib. Further studies will optimize patient target selection and identify the best treatment combinations.-
dc.languageeng-
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jhep-
dc.relation.ispartofJournal of Hepatology-
dc.subjectSorafenib resistance-
dc.subjectRegorafenib-
dc.subjectLiver cancer-
dc.subjectANXA3-
dc.subjectAntibody therapy-
dc.titleEfficacy of annexin A3 blockade in sensitizing hepatocellular carcinoma to sorafenib and regorafenib-
dc.typeArticle-
dc.identifier.emailTong, M: caroltm@hku.hk-
dc.identifier.emailZhou, L: lenazhou@connect.hku.hk-
dc.identifier.emailLui Kau, WF: kwflui@hku.hk-
dc.identifier.emailNgan, ES: engan@hku.hk-
dc.identifier.emailLo, CM: chungmlo@hkucc.hku.hk-
dc.identifier.emailMan, K: kwanman@hku.hk-
dc.identifier.emailMa, SKY: stefma@hku.hk-
dc.identifier.authorityTong, M=rp02568-
dc.identifier.authorityNgan, ES=rp00422-
dc.identifier.authorityLo, CM=rp00412-
dc.identifier.authorityMan, K=rp00417-
dc.identifier.authorityMa, SKY=rp00506-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.jhep.2018.05.034-
dc.identifier.pmid29885413-
dc.identifier.scopuseid_2-s2.0-85050184824-
dc.identifier.hkuros288692-
dc.identifier.volume69-
dc.identifier.issue4-
dc.identifier.spage826-
dc.identifier.epage839-
dc.identifier.isiWOS:000444890900014-
dc.publisher.placeNetherlands-
dc.relation.projectA Multidisciplinary Study on CD133 Liver Cancer Stem Cells: Molecular Mechanisms, Clinical Relevance and Therapeutic Implications-
dc.identifier.issnl0168-8278-

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