The Roles of Epigenetic Regulation and the Tumor Microenvironment in the Mechanism of Resistance to Systemic Therapy in Hepatocellular Carcinoma
Primary liver cancer is the sixth most common cancer and the third most common cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is a major histologic type with a poor prognosis owing to the difficulty in early detection, the chemotherapy resistance, and the high recurrence ra...
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| Published in | International Journal of Molecular Sciences Vol. 24; no. 3; p. 2805 |
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| Main Authors | , , , , |
| Format | Journal Article |
| Language | English |
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MDPI AG
01.02.2023
MDPI |
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| Abstract | Primary liver cancer is the sixth most common cancer and the third most common cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is a major histologic type with a poor prognosis owing to the difficulty in early detection, the chemotherapy resistance, and the high recurrence rate of the disease. Despite recent advancements in HCC prevention and diagnosis, over 50% of patients are diagnosed at Barcelona Clinic Liver Cancer Stage B or C. Systemic therapies are recommended for unresectable HCC (uHCC) with major vascular invasion, extrahepatic metastases, or intrahepatic lesions that have a limited response to transcatheter arterial chemoembolization, but the treatment outcome tends to be unsatisfactory due to acquired drug resistance. Elucidation of the mechanisms underlying the resistance to systemic therapies and the appropriate response strategies to solve this issue will contribute to improved outcomes in the multidisciplinary treatment of uHCC. In this review, we summarize recent findings on the mechanisms of resistance to drugs such as sorafenib, regorafenib, and lenvatinib in molecularly targeted therapy, with a focus on epigenetic regulation and the tumor microenvironment and outline the approaches to improve the therapeutic outcome for patients with advanced HCC. |
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| AbstractList | Primary liver cancer is the sixth most common cancer and the third most common cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is a major histologic type with a poor prognosis owing to the difficulty in early detection, the chemotherapy resistance, and the high recurrence rate of the disease. Despite recent advancements in HCC prevention and diagnosis, over 50% of patients are diagnosed at Barcelona Clinic Liver Cancer Stage B or C. Systemic therapies are recommended for unresectable HCC (uHCC) with major vascular invasion, extrahepatic metastases, or intrahepatic lesions that have a limited response to transcatheter arterial chemoembolization, but the treatment outcome tends to be unsatisfactory due to acquired drug resistance. Elucidation of the mechanisms underlying the resistance to systemic therapies and the appropriate response strategies to solve this issue will contribute to improved outcomes in the multidisciplinary treatment of uHCC. In this review, we summarize recent findings on the mechanisms of resistance to drugs such as sorafenib, regorafenib, and lenvatinib in molecularly targeted therapy, with a focus on epigenetic regulation and the tumor microenvironment and outline the approaches to improve the therapeutic outcome for patients with advanced HCC. Primary liver cancer is the sixth most common cancer and the third most common cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is a major histologic type with a poor prognosis owing to the difficulty in early detection, the chemotherapy resistance, and the high recurrence rate of the disease. Despite recent advancements in HCC prevention and diagnosis, over 50% of patients are diagnosed at Barcelona Clinic Liver Cancer Stage B or C. Systemic therapies are recommended for unresectable HCC (uHCC) with major vascular invasion, extrahepatic metastases, or intrahepatic lesions that have a limited response to transcatheter arterial chemoembolization, but the treatment outcome tends to be unsatisfactory due to acquired drug resistance. Elucidation of the mechanisms underlying the resistance to systemic therapies and the appropriate response strategies to solve this issue will contribute to improved outcomes in the multidisciplinary treatment of uHCC. In this review, we summarize recent findings on the mechanisms of resistance to drugs such as sorafenib, regorafenib, and lenvatinib in molecularly targeted therapy, with a focus on epigenetic regulation and the tumor microenvironment and outline the approaches to improve the therapeutic outcome for patients with advanced HCC.Primary liver cancer is the sixth most common cancer and the third most common cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is a major histologic type with a poor prognosis owing to the difficulty in early detection, the chemotherapy resistance, and the high recurrence rate of the disease. Despite recent advancements in HCC prevention and diagnosis, over 50% of patients are diagnosed at Barcelona Clinic Liver Cancer Stage B or C. Systemic therapies are recommended for unresectable HCC (uHCC) with major vascular invasion, extrahepatic metastases, or intrahepatic lesions that have a limited response to transcatheter arterial chemoembolization, but the treatment outcome tends to be unsatisfactory due to acquired drug resistance. Elucidation of the mechanisms underlying the resistance to systemic therapies and the appropriate response strategies to solve this issue will contribute to improved outcomes in the multidisciplinary treatment of uHCC. In this review, we summarize recent findings on the mechanisms of resistance to drugs such as sorafenib, regorafenib, and lenvatinib in molecularly targeted therapy, with a focus on epigenetic regulation and the tumor microenvironment and outline the approaches to improve the therapeutic outcome for patients with advanced HCC. |
| Author | Asahiro Morishita Kyoko Oura Sae Hamaya Tsutomu Masaki Koji Fujita |
| AuthorAffiliation | Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita 761-0793, Kagawa, Japan |
| AuthorAffiliation_xml | – name: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita 761-0793, Kagawa, Japan |
| Author_xml | – sequence: 1 givenname: Kyoko orcidid: 0000-0002-9531-7240 surname: Oura fullname: Oura, Kyoko – sequence: 2 givenname: Asahiro orcidid: 0000-0002-0760-3045 surname: Morishita fullname: Morishita, Asahiro – sequence: 3 givenname: Sae surname: Hamaya fullname: Hamaya, Sae – sequence: 4 givenname: Koji surname: Fujita fullname: Fujita, Koji – sequence: 5 givenname: Tsutomu surname: Masaki fullname: Masaki, Tsutomu |
| BackLink | https://cir.nii.ac.jp/crid/1871146592786534144$$DView record in CiNii https://www.ncbi.nlm.nih.gov/pubmed/36769116$$D View this record in MEDLINE/PubMed |
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| CitedBy_id | crossref_primary_10_1111_hepr_14089 crossref_primary_10_1016_j_biopha_2024_117343 crossref_primary_10_3390_biomedicines11041166 crossref_primary_10_4254_wjh_v16_i5_716 crossref_primary_10_1371_journal_pone_0301663 crossref_primary_10_1016_j_biopha_2023_115561 crossref_primary_10_1016_j_gande_2024_06_001 crossref_primary_10_62347_YAVK1315 crossref_primary_10_1016_j_ncrna_2024_12_002 crossref_primary_10_3390_cancers16040680 crossref_primary_10_62347_EAFU3015 crossref_primary_10_1111_liv_15953 crossref_primary_10_1007_s00432_023_04899_5 crossref_primary_10_3389_fonc_2025_1570647 crossref_primary_10_1007_s00432_023_05370_1 crossref_primary_10_2147_IJN_S460844 crossref_primary_10_3390_metabo14060325 crossref_primary_10_1016_j_canlet_2025_217472 crossref_primary_10_3389_fimmu_2023_1232390 crossref_primary_10_1007_s12032_024_02529_9 crossref_primary_10_3389_fimmu_2024_1444091 |
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| Keywords | immune checkpoint inhibitor lenvatinib sorafenib tyrosine kinase molecular target agent drug resistance regorafenib tumor microenvironment systemic therapy hepatocellular carcinoma |
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| Title | The Roles of Epigenetic Regulation and the Tumor Microenvironment in the Mechanism of Resistance to Systemic Therapy in Hepatocellular Carcinoma |
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