EGFR activation limits the response of liver cancer to lenvatinib

Jin, Haojie; Shi, Yaoping; Lv, Yuanyuan; Yuan, Shengxian; Ramirez, Christel; Lieftink, Cor; Wang, Liqin; Wang, Siying; Wang, Cun; Dias, Matheus Henrique; Jochems, Fleur; Yang, Yuan; Bosma, Astrid; Hijmans, E. Marielle; Groot, Marnix H. P. de; Vegna, Serena; Cui, Dan; Zhou, Yangyang; Jing, Ling; Wang, Hui; Guo, Yuchen; Zheng, Xingling; Isima, Nikita; Wu, Huawei; Sun, Chong; Beijersbergen, Roderick L.; Akkari, Leila; Zhou, Weiping; Zhai, Bo; Qin, Wenxin; Bernards, R.

doi:10.1038/s41586-021-03741-7

Cited by 198 publications

(139 citation statements)

References 33 publications

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“…However, lenvatinib alone could inhibit HCC cancer stem-like cells through FGFR1-3 signaling, but not FGFR4 signaling [ 35 ]. Interestingly, lenvatinib could also increase the expression of EGFR, as previously reported [ 36 , 37 ]. The activation of EGFR may contribute to sorafenib or lenvatinib resistance.…”

Section: Discussionsupporting

confidence: 79%

“…The activation of EGFR may contribute to sorafenib or lenvatinib resistance. The combination therapy of lenvatinib and gefitinib (an EGFR inhibitor) may be an option for the approximately 50% of advanced HCC patients with high EGFR expression [ 37 ]. Combination therapy or new kinase inhibitors (such as ERK inhibitors) may represent a promising strategy for sorafenib-resistant HCC patients.…”

Section: Discussionmentioning

confidence: 99%

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Evaluating the Effect of Lenvatinib on Sorafenib-Resistant Hepatocellular Carcinoma Cells

Shi

Iwama

Fujita

et al. 2021

IJMS

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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.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Evaluating the Effect of Lenvatinib on Sorafenib-Resistant Hepatocellular Carcinoma Cells

Shi

Iwama

Fujita

et al. 2021

IJMS

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“…In addition, cancer had the most significant term frequency in the literature because it is still the greatest challenge in terms of treatment ( Vasan et al, 2019 ). Cancer treatment is the most prominent topic for high-impact studies in this field ( Jin et al, 2021 ; Li et al, 2020 ; Liu et al, 2020 ). We also found that oxidative stress and inflammation were the core themes, which predicted targets of drug therapy or drug discovery in the future ( Reuter et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Trends of High-Impact Studies in Pharmacology and Pharmacy: A Cross-Sectional Study

et al. 2021

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Objective: To investigate the trends of high-impact studies in pharmacology and pharmacy research and to provide evidence for future research in the field of pharmacology and pharmacy.Methods: A cross-sectional study was performed to understand the current status of high-impact studies (top 1%) in pharmacology and pharmacy research via InCites tool based on Web of Science Core Collection. VOSViewer software was used to visualize the results. The outcomes included development trends, countries, subject areas, research institutes, collaborative networks, and subject terms.Results: We found 4,273 high-impact (top 1%) studies between 2011 and 2020 in the field of pharmacology and pharmacy. The number of studies increased from 366 in 2011 to 510 in 2020. These studies were mainly distributed in the following Web of Science subject categories: pharmacology and pharmacy (n = 4,188); neurosciences (n = 397); chemistry, multidisciplinary (n = 359); chemistry, medicinal (n = 314); microbiology (n = 301); biotechnology and applied microbiology (n = 280). These studies were cited in 646,855 studies from more than 100 Web of Science subject categories, and studies in pharmacology pharmacy accounted for the largest share of these citations. The top three countries that contributed the highest number of studies were the United States, United Kingdom, and China. The top three institutions that contributed the highest number of studies in the United States were the University of California System, the National Institutes of Health (NIH), and Harvard University. The top research collaborative circle was from universities in the United States. The top international collaborative circle was from universities from the United States, United Kingdom, Australia, and China. The subject-term analysis indicated that cancer was still the top disease, NF-κB was the top signaling pathway, and drug-delivery and nanoparticles were the top methods.Conclusion: The high-impact studies in pharmacology and pharmacy research have grown over time. The United States, the United Kingdom, and China are the top countries that contributed the high-impact studies. Cancer is still the greatest challenge in the field of disease treatment. It calls for more international collaboration in pharmacology and pharmacy research, which will help discover novel drugs.

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“…The human normal liver cell line HL-7702 and HCC cell lines (SK-Hep1 and Huh7) were cultured in a DMEM medium containing 10% FBS in a 5% CO 2 incubator at 37 °C. In addition, huh7 cells were treated by Lenvatinib (HY-10981, MCE) with different concentrations (0, 0.5, 1, 5, 10 μM) for 48 h based on the previous study (Jin et al, 2021). RNA extraction and quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR).…”

Section: Cell Culture and Drug Treatmentmentioning

confidence: 99%

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EGFR activation limits the response of liver cancer to lenvatinib

Cited by 198 publications

References 33 publications

Evaluating the Effect of Lenvatinib on Sorafenib-Resistant Hepatocellular Carcinoma Cells

Evaluating the Effect of Lenvatinib on Sorafenib-Resistant Hepatocellular Carcinoma Cells

Trends of High-Impact Studies in Pharmacology and Pharmacy: A Cross-Sectional Study

Table1.XLSX

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