Evaluating the Effect of Lenvatinib on Sorafenib-Resistant Hepatocellular Carcinoma Cells
Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related deaths worldwide. Sorafenib has been used as a first-line systemic treatment for over a decade. However, resistance to sorafenib limits patient response and presents a major hurdle during HCC treatment. Lenvatinib has been a...
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MDPI AG
2021-12-01
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| Series: | International Journal of Molecular Sciences |
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| author | Tingting Shi Hisakazu Iwama Koji Fujita Hideki Kobara Noriko Nishiyama Shintaro Fujihara Yasuhiro Goda Hirohito Yoneyama Asahiro Morishita Joji Tani Mari Yamada Mai Nakahara Kei Takuma Tsutomu Masaki |
| author_facet | Tingting Shi Hisakazu Iwama Koji Fujita Hideki Kobara Noriko Nishiyama Shintaro Fujihara Yasuhiro Goda Hirohito Yoneyama Asahiro Morishita Joji Tani Mari Yamada Mai Nakahara Kei Takuma Tsutomu Masaki |
| author_sort | Tingting Shi |
| collection | DOAJ |
| description | Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related deaths worldwide. Sorafenib has been used as a first-line systemic treatment for over a decade. However, resistance to sorafenib limits patient response and presents a major hurdle during HCC treatment. Lenvatinib has been approved as a first-line systemic treatment for advanced HCC and is the first agent to achieve non-inferiority against sorafenib. Therefore, in the present study, we evaluated the inhibition efficacy of lenvatinib in sorafenib-resistant HCC cells. Only a few studies have been conducted on this topic. Two human HCC cell lines, Huh-7 and Hep-3B, were used to establish sorafenib resistance, and in vitro and in vivo studies were employed. Lenvatinib suppressed sorafenib-resistant HCC cell proliferation mainly by inducing G1 cell cycle arrest through ERK signaling. Hep-3B sorafenib-resistant cells showed partial cross-resistance to lenvatinib, possibly due to the contribution of poor autophagic responsiveness. Overall, the findings suggest that the underlying mechanism of lenvatinib in overcoming sorafenib resistance in HCC involves FGFR4-ERK signaling. Lenvatinib may be a suitable second-line therapy for unresectable HCC patients who have developed sorafenib resistance and express FGFR4. |
| first_indexed | 2024-03-10T04:52:52Z |
| format | Article |
| id | doaj.art-fc547ebd8a354b4db2a2e2b44a15f49c |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:52:52Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-fc547ebd8a354b4db2a2e2b44a15f49c2023-11-23T02:32:42ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-12-0122231307110.3390/ijms222313071Evaluating the Effect of Lenvatinib on Sorafenib-Resistant Hepatocellular Carcinoma CellsTingting Shi0Hisakazu Iwama1Koji Fujita2Hideki Kobara3Noriko Nishiyama4Shintaro Fujihara5Yasuhiro Goda6Hirohito Yoneyama7Asahiro Morishita8Joji Tani9Mari Yamada10Mai Nakahara11Kei Takuma12Tsutomu Masaki13Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki 761-0793, JapanLife Science Research Center, Kagawa University, 1750-1 Ikenobe, Miki 761-0793, JapanDepartment of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki 761-0793, JapanDepartment of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki 761-0793, JapanDepartment of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki 761-0793, JapanDepartment of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki 761-0793, JapanDepartment of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki 761-0793, JapanDepartment of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki 761-0793, JapanDepartment of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki 761-0793, JapanDepartment of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki 761-0793, JapanDepartment of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki 761-0793, JapanDepartment of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki 761-0793, JapanDepartment of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki 761-0793, JapanDepartment of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki 761-0793, JapanHepatocellular carcinoma (HCC) is one of the major causes of cancer-related deaths worldwide. Sorafenib has been used as a first-line systemic treatment for over a decade. However, resistance to sorafenib limits patient response and presents a major hurdle during HCC treatment. Lenvatinib has been approved as a first-line systemic treatment for advanced HCC and is the first agent to achieve non-inferiority against sorafenib. Therefore, in the present study, we evaluated the inhibition efficacy of lenvatinib in sorafenib-resistant HCC cells. Only a few studies have been conducted on this topic. Two human HCC cell lines, Huh-7 and Hep-3B, were used to establish sorafenib resistance, and in vitro and in vivo studies were employed. Lenvatinib suppressed sorafenib-resistant HCC cell proliferation mainly by inducing G1 cell cycle arrest through ERK signaling. Hep-3B sorafenib-resistant cells showed partial cross-resistance to lenvatinib, possibly due to the contribution of poor autophagic responsiveness. Overall, the findings suggest that the underlying mechanism of lenvatinib in overcoming sorafenib resistance in HCC involves FGFR4-ERK signaling. Lenvatinib may be a suitable second-line therapy for unresectable HCC patients who have developed sorafenib resistance and express FGFR4.https://www.mdpi.com/1422-0067/22/23/13071lenvatinibsorafenib-resistanthepatocellular carcinomaFGFR4autophagymicroRNA |
| spellingShingle | Tingting Shi Hisakazu Iwama Koji Fujita Hideki Kobara Noriko Nishiyama Shintaro Fujihara Yasuhiro Goda Hirohito Yoneyama Asahiro Morishita Joji Tani Mari Yamada Mai Nakahara Kei Takuma Tsutomu Masaki Evaluating the Effect of Lenvatinib on Sorafenib-Resistant Hepatocellular Carcinoma Cells International Journal of Molecular Sciences lenvatinib sorafenib-resistant hepatocellular carcinoma FGFR4 autophagy microRNA |
| title | Evaluating the Effect of Lenvatinib on Sorafenib-Resistant Hepatocellular Carcinoma Cells |
| title_full | Evaluating the Effect of Lenvatinib on Sorafenib-Resistant Hepatocellular Carcinoma Cells |
| title_fullStr | Evaluating the Effect of Lenvatinib on Sorafenib-Resistant Hepatocellular Carcinoma Cells |
| title_full_unstemmed | Evaluating the Effect of Lenvatinib on Sorafenib-Resistant Hepatocellular Carcinoma Cells |
| title_short | Evaluating the Effect of Lenvatinib on Sorafenib-Resistant Hepatocellular Carcinoma Cells |
| title_sort | evaluating the effect of lenvatinib on sorafenib resistant hepatocellular carcinoma cells |
| topic | lenvatinib sorafenib-resistant hepatocellular carcinoma FGFR4 autophagy microRNA |
| url | https://www.mdpi.com/1422-0067/22/23/13071 |
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