scholarly journals CASK Silence Enhances Chemosensitivity of Hepatocellular Carcinoma Through activating Apoptosis, Inducing JNK/c-Jun-Mediated Autophagic Cell Death and Decreasing ABCG2

2021 ◽  
Author(s):  
BiSha Ding ◽  
Chang Bao ◽  
Luqi Jin ◽  
Liang Xu ◽  
Zhijun Dai ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Cell Death ◽  
Molecular Mechanisms ◽  
Autophagic Cell Death ◽  
Cell Counting ◽  
Advanced Hepatocellular Carcinoma ◽  
Sorafenib Treatment

Abstract Background: Advanced hepatocellular carcinoma (HCC) patients usually fail to be treated because of drug resistance, including sorafenib. Methods: The expression and prognostic role of calcium/calmodulin-dependent serine protein kinase (CASK) in HCC were assessed by combination of bioinformatic analysis and experimental validation. The effects of CASK in regulating proliferation, apoptosis and drug resistance of HCC cells in vitro and in vivo were investigated using gain- or loss-of-function strategies by performing lots of specific methods including Cell Counting kit-8 (CCK8), colony formation assay, flow cytometry, transmission electron microscopy, immunofluorescent confocal laser microscopy and tumor xenograft experiments, immunohistochemistry staining. Moreover, the underlying molecular mechanisms responsible for CASK’s functions in HCC were also explored. Results: Currently, we discovered that CASK was positively associated with sorafenib resistance of HCC in vitro and in vivo, and was significantly related with poor prognosis in HCC. Moreover, inhibition of CASK can increase the effect of sorafenib partially by promoting apoptosis and autophagy, while CASK overexpression presented the opposite results. Besides, all the pan-caspase inhibitor Z-VAD-FMK, autophagy inhibitor 3-Methyladenine (3-MA) and small interfering RNA (siRNA) of LC3B reversed CASK knockout-induced effects with sorafenib treatment, suggesting that both apoptosis and autophagy were involved in CASK-mediated above functions and autophagy played a pro-death role in this research. Intriguingly, similar results were observed in vivo. In molecular level, CASK knockout activated the c-Jun N-terminal kinase (JNK) pathway, and treatment with JNK inhibitor SP600125 or transiently transfected with si-JNK significantly attenuated CASK knockout-mediated autophagic cell death. Besides, knockout of CASK dramatically inhibited the expression of ATP binding cassette subfamily G member 2 (ABCG2) and reversed of multidrug-resistance (MDR) of HCC. Conclusions: Collectively, all these results together indicated that CASK might be a promising biomarker for HCC patients and a potential therapeutic target for relieving drug resistance of HCC.

scholarly journals Epigenetic regulation of ferroptosis via ETS1/miR-23a-3p/ACSL4 axis mediates sorafenib resistance in human hepatocellular carcinoma

2022 ◽  
Vol 41 (1) ◽  
Author(s):  
Yuanjun Lu ◽  
Yau-Tuen Chan ◽  
Hor-Yue Tan ◽  
Cheng Zhang ◽  
Wei Guo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Bioinformatics Analyses ◽  
Sorafenib Treatment ◽  
Hcc Cells

Abstract Background Drug resistance to sorafenib greatly limited the benefits of treatment in patients with hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) participate in the development of drug resistance. The key miRNA regulators related to the clinical outcome of sorafenib treatment and their molecular mechanisms remain to be identified. Methods The clinical significance of miRNA-related epigenetic changes in sorafenib-resistant HCC was evaluated by analyzing publicly available databases and in-house human HCC tissues. The biological functions of miR-23a-3p were investigated both in vitro and in vivo. Proteomics and bioinformatics analyses were conducted to identify the mechanisms that regulating miR-23a-3p. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were used to validate the binding relationship of miR-23a-3p and its targets. Results We found that miR-23a-3p was the most prominent miRNA in HCC, which was overexpressed in sorafenib non-responders and indicated poor survival and HCC relapse. Sorafenib-resistant cells exhibited increased miR-23a-3p transcription in an ETS Proto-Oncogene 1 (ETS1)-dependent manner. CRISPR-Cas9 knockout of miR-23a-3p improved sorafenib response in HCC cells as well as orthotopic HCC tumours. Proteomics analysis suggested that sorafenib-induced ferroptosis was the key pathway suppressed by miR-23a-3p with reduced cellular iron accumulation and lipid peroxidation. MiR-23a-3p directly targeted the 3′-untranslated regions (UTR) of ACSL4, the key positive regulator of ferroptosis. The miR-23a-3p inhibitor rescued ACSL4 expression and induced ferrotoptic cell death in sorafenib-treated HCC cells. The co-delivery of ACSL4 siRNA and miR-23a-3p inhibitor abolished sorafenib response. Conclusion Our study demonstrates that ETS1/miR-23a-3p/ACSL4 axis contributes to sorafenib resistance in HCC through regulating ferroptosis. Our findings suggest that miR-23a-3p could be a potential target to improve sorafenib responsiveness in HCC patients.

scholarly journals Crizotinib and Doxorubicin Cooperatively Reduces Drug Resistance by Mitigating MDR1 to Increase Hepatocellular Carcinoma Cells Death

2021 ◽  
Vol 11 ◽  
Author(s):  
Ming Shao ◽  
Run Shi ◽  
Zhen-Xing Gao ◽  
Shan-Shan Gao ◽  
Jing-Feng Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Cell Death ◽  
Kinase Inhibitor ◽  
Multiple Drug Resistance ◽  
Autophagic Cell Death ◽  
Multiple Drug ◽  
Parp 1

As the sixth most lethal cancers worldwide, hepatocellular carcinoma (HCC) has been treated with doxorubicin (Dox) for decades. However, chemotherapy resistance, especially for Dox is an even more prominent problem due to its high cardiotoxicity. To find a regimen to reduce Dox resistance, and identify the mechanisms behind it, we tried to identify combination of drugs that can overcome drug resistance by screening tyrosine kinase inhibitor(s) with Dox with various HCC cell lines in vitro and in vivo. We report here that combination of Crizo and Dox has a synergistic effect on inducing HCC cell death. Accordingly, Crizo plus Dox increases Dox accumulation in nucleus 3-16 times compared to Dox only; HCC cell death enhanced at least 50% in vitro and tumor weights reduced ranging from 35 to 65%. Combining these two drugs reduces multiple drug resistance 1 (MDR1) protein as a result of activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK), which phosphorylates eIF2α, leading to protein translational repression. Additionally, PERK stimulation activates C-Jun terminal kinase (JNK), resulting in accumulation of unfused autophagosome to enhance autophagic cell death via Poly-ADP-ribosyltransferase (PARP-1) cleavage. When the activity of PERK or JNK is blocked, unfused autophagosome is diminished, cleaved PARP-1 is reduced, and cell death is abated. Therefore, Crizo plus Dox sensitize HCC drug resistance by engaging PERK-p- eIF2α-MDR1, and kill HCC cells by engaging PERK-JNK- autophagic cell death pathways. These newly discovered mechanisms of Crizo plus Dox not only provide a potential treatment for HCC but also point to an approach to overcome MDR1 related drug resistance in other cancers.

scholarly journals Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Lai Wei ◽  
Derek Lee ◽  
Cheuk-Ting Law ◽  
Misty Shuo Zhang ◽  
Jialing Shen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Kinase Inhibitors ◽  
Standard Treatment ◽  
Advanced Hepatocellular Carcinoma ◽  
Library Screening ◽  
Sorafenib Treatment ◽  
Genome Wide ◽  
Phosphoglycerate Dehydrogenase

Abstract Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC). However, the development of drug resistance is common. By using genome-wide CRISPR/Cas9 library screening, we identify phosphoglycerate dehydrogenase (PHGDH), the first committed enzyme in the serine synthesis pathway (SSP), as a critical driver for Sorafenib resistance. Sorafenib treatment activates SSP by inducing PHGDH expression. With RNAi knockdown and CRISPR/Cas9 knockout models, we show that inactivation of PHGDH paralyzes the SSP and reduce the production of αKG, serine, and NADPH. Concomitantly, inactivation of PHGDH elevates ROS level and induces HCC apoptosis upon Sorafenib treatment. More strikingly, treatment of PHGDH inhibitor NCT-503 works synergistically with Sorafenib to abolish HCC growth in vivo. Similar findings are also obtained in other FDA-approved tyrosine kinase inhibitors (TKIs), including Regorafenib or Lenvatinib. In summary, our results demonstrate that targeting PHGDH is an effective approach to overcome TKI drug resistance in HCC.

scholarly journals Targeting Positive Cofactor 4 induces autophagic cell death in MYC-expressing diffuse large B cell lymphoma

2021 ◽  
Author(s):  
Le Ma ◽  
Qiang Gong ◽  
Zelin Chen ◽  
Yu Wang ◽  
Xu Tan ◽  
...  
Keyword(s):  
Cell Death ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Autophagic Cell Death ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background: The MYC-expressing diffuse large B-cell lymphoma (DLBCL) is one of the refractory lymphomas. The pathogenesis of MYC-expressing DLBCL is still unclear, and there is a lack of effective therapy. In this study, we have explored the clinical significance and the molecular mechanisms of transcription co-activator 4 (PC4) in MYC-expressing DLBCL.Methods: We investigated PC4 expression in 54 cases of DLBCL patients’ tissues and matched normal specimens, and studied the molecular mechanisms of PC4 in MYC-expressing DLBCL both in vitro and in vivo.Results: We reported for the first time that targeting c-Myc could induce autophagic cell death in MYC-expressing DLBCL cell lines. We next characterized that PC4 was an upstream regulator of c-Myc, and PC4 was overexpressed in DLBCL and was closely related to clinical staging, prognosis and c-Myc expression. Further, our in vivo and in vitro studies revealed that PC4 knockdown could induce autophagic cell death of MYC-expressing DLBCL. And inhibition of c-Myc mediated aerobic glycolysis and activation of AMPK / mTOR signaling pathway were responsible for the autophagic cell death induced by PC4 knockdown in MYC-expressing DLBCL. Through the CHIP, DLRTM and EMSA assay, we also found that PC4 exerted its oncogenic functions by directly binding to c-Myc promoters.Conclusions: PC4 exerts its oncogenic functions by directly binding to c-Myc promoters. Inhibition of PC4 can induce autophagic cell death of MYC-expressing DLBCL. Our study provides novel insights into the functions and mechanisms of PC4 in MYC-expressing DLBCL, and suggests that PC4 might be a promising therapeutic target for MYC-expressing DLBCL.

scholarly journals Engineered Exosomes for the Targeted Delivery of a Novel Therapeutic Cargo to Enhance Sorafenib-Mediated Ferroptosis in Hepatocellular Carcinoma.

2021 ◽  
Author(s):  
Xiaoju Li ◽  
Qianqian Yu ◽  
Xinyan Guo ◽  
Chenlin Liu ◽  
Runze Zhao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Targeted Delivery ◽  
Rna Recognition Motif ◽  
Advanced Hepatocellular Carcinoma ◽  
Rna Recognition ◽  
Sorafenib Treatment ◽  
Recognition Motif ◽  
Interfering Rna

Abstract Background Sorafenib is one of the few effective first-line drugs approved for the treatment of advanced hepatocellular carcinoma (HCC). However, the development of drug resistance is common among individuals with HCC. Thus, there is an urgent need to solve this problem. Results Recent evidence indicated that the anticancer activity of sorafenib mainly relies on the induction of ferroptosis. In our study, genes that suppress ferroptosis, especially GPX4 and DHODH, were enriched in sorafenib-resistant cells and primary tissues and were associated with poor prognosis of HCC patients who received sorafenib treatment. Therefore, silencing GPX4 and DHODH might be a novel and effective strategy to overcome sorafenib resistance. Here, a novel ferroptosis inducer comprising a multiplex small interfering RNA (multi-siRNA) capable of simultaneously silencing GPX4 and DHODH was created. Then, exosomes with high multi-siRNA loading and HCC-specific targeting were established by fusing the SP94 peptide and the N-terminal RNA recognition motif (RRM) of U1-A with the exosomal membrane protein Lamp2b. The results from the in vitro and in vivo experiments indicate that this tumor-targeting nanodelivery system (ExoSP94−lamp2b−RRM-multi-siRNA) could enhance sorafenib-induced ferroptosis and overcome sorafenib resistance, which might open a new avenue for clinically overcoming sorafenib resistance. Conclusions We designed HCC-targeted exosomes (ExoSP94−Lamp2b−RRM) that can deliver a novel ferroptosis inducer. Our data show that ExoSP94−lamp2b−RRM-multi-siRNA could enhance sorafenib-induced ferroptosis by silencing GPX4 and DHODH expression and consequently increase HCC sensitivity to sorafenib. This is the first study to describe the use of engineered exosomes to overcome acquired sorafenib resistance with respect to ferroptosis.

scholarly journals Targeting Positive Cofactor 4 Induces Autophagic Cell Death In MYC-Expressing Diffuse Large B Cell Lymphoma

2021 ◽  
Author(s):  
Le Ma ◽  
Qiang Gong ◽  
Jianlin Fu ◽  
Mingling Xie ◽  
Peng Luo ◽  
...  
Keyword(s):  
Cell Death ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Autophagic Cell Death ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background: The MYC-expressing diffuse large B-cell lymphoma (DLBCL) is one of the refractory lymphomas. The pathogenesis of MYC-expressing DLBCL is still unclear, and there is a lack of effective therapy. In this study, we have explored the clinical significance and the molecular mechanisms of transcription co-activator 4 (PC4) in MYC-expressing DLBCL.Methods: We investigated PC4 expression in 54 cases of DLBCL patients’ tissues and matched normal specimens, and studied the molecular mechanisms of PC4 in MYC-expressing DLBCL both in vitro and in vivo.Results: We reported for the first time that targeting c-Myc could induce autophagic cell death in MYC-expressing DLBCL cell lines. We next characterized that PC4 was an upstream regulator of c-Myc, and PC4 was overexpressed in DLBCL and was closely related to clinical staging, prognosis and c-Myc expression. Further, our in vivo and in vitro studies revealed that PC4 knockdown could induce autophagic cell death of MYC-expressing DLBCL. And inhibition of c-Myc mediated aerobic glycolysis and activation of AMPK / mTOR signaling pathway were responsible for the autophagic cell death induced by PC4 knockdown in MYC-expressing DLBCL. Through the DLRTM and EMSA assay, we also found that PC4 exerted its oncogenic functions by directly binding to c-Myc promoters.Conclusions: PC4 exerts its oncogenic functions by directly binding to c-Myc promoters. Inhibition of PC4 can induce autophagic cell death of MYC-expressing DLBCL. Our study provides novel insights into the functions and mechanisms of PC4 in MYC-expressing DLBCL, and suggests that PC4 might be a promising therapeutic target for MYC-expressing DLBCL.

Improved sorafenib activity on hepatocellular carcinoma in Notch3 silenced in vivo and in vitro models.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3061-3061
Author(s):  
Michele Baglioni ◽  
Catia Giovannini ◽  
Laura Gramantieri ◽  
Marco Baron Toaldo ◽  
Cristiano Ventrucci ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Fate ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Randomized Clinical Trials ◽  
Advanced Stage ◽  
Sorafenib Treatment ◽  
Cellular Models

3061 Background: Sorafenib is the only approved drug for the treatment of the advanced stage of HCC. Although its efficacy has been proven with randomized clinical trials, the clinical benefit seen in overall survival for advanced HCC patients treated with sorafenib could be improved. New molecules or combination of novel targeted agents to improve sorafenib efficacy for advanced stage HCC patients are needed. Notch genes are a family of receptors involved in many cell fate regulations, their expression has been found altered in many tumors, including HCC. The aim of this study was to study the combination of sorafenib and Notch3 signaling inhibition to improve sorafenib’s therapeutic effect. Methods: HepG2 and Huh7 cellular models were used for Notch3 stable silencing by retroviral introduction of specific interfering RNAs Xenograft models in both Notch3 stable shRNA cell lines have been developed using NOD/SCID mice. Animals bearing tumors were treated with 60 mg/kg of sorafenib for 21 consecutive days. Notch3, p21 and pGSK3βSer9 protein expression were also analyzed in 20 human HCCs. Results: Notch3 silencing (shN3) in HuH7 and HepG2 cell lines treated with sorafenib showed an increase in cell death (3.8 to 5 fold increase) when shN3 cell lines were compared with their relative controls (GL2). A difference in tumor growth was observed between GL2 negative control vs shN3 xenografts in both HepG2 and Huh7 after 21 days of sorafenib treatment. Two tailed student’s t test (shN3 vs GL2) P=0,04 and P=0,01 for Huh7 and HepG2 respectively. Molecular investigations have shown the involvement of p21 and GSK3β in the enhanced response to sorafenib in Notch 3 silenced models. A significant inverse correlation between Notch3 and pGSK3βSer9 proteins accumulation (Spearman ρ= -0.666) (p < 0.01) and a direct correlation between Notch3 and p21 proteins expression (Spearman ρ= 0.681) (p < 0.01) was found in HCC samples obtained from patients. Conclusion: Our preclincal findings outline the effect of combined Notch3 inhibition and sorafenib. The molecular mechanisms responsible for sorafenib induced cell death associated with Notch3 silencing relays on inhibition of p21/CDKN1A and GSK3βSer9. This study is supported by a grant from Bayer Healthcare, Italy.

scholarly journals NT157 Inhibits Hepatocellular Carcinoma Growth and Sensitizes Cells to Sorafenib

2021 ◽  
Author(s):  
Yu Wang ◽  
Si-Zhe Yu ◽  
Shi-Rong Zhang ◽  
Jia Hou ◽  
Min Jiao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Mapk Signaling ◽  
Advanced Hepatocellular Carcinoma ◽  
Downstream Signaling ◽  
Potential Strategy ◽  
Induced Apoptosis ◽  
Hcc Cells

Abstract Background: Sorafenib has been recognized as the standard therapy for advanced hepatocellular carcinoma (HCC). Besides, efficacy of sorafenib was unsatisfactory and vast patients are resistant to sorafenib. Thus, molecular mechanisms underlying regulation of sorafenib resistance and seeking potential strategy to improve its efficacy have attracted much attention. As a small-molecule inhibitor of IGF-1R, NT157 has potent antitumor activity against some human cancers. However, whether NT157 has potential anti-tumor effects and its molecular mechanisms in HCC remain poorly understood. Methods: We assessed the effects and explored the mechanism of NT157 and sorafenib as single agents or in combination with sorafenib in HCC cells and mouse model. Further, we further demonstrated that NT157 reversed resistance to sorafenib in HCC.Results: Here, we found NT157 inhibited HCC growth and induced apoptosis in vitro and in vivo. In terms of mechanism, NT157 phosphorylated IRS-1 through ERK-MAPK signaling to be degraded by the ubiquitin-proteasome pathway, lowered p-AKT to deactivate IGF-1R signaling to inhibit proliferation and induce apoptosis. Surprisingly, we further demonstrated that NT157 acted synergistically with sorafenib to inhibit proliferation and contributed to sensitize HCC cells to sorafenib by down-regulation of p-AKT. Conclusions: Overall, our findings provide a translational rationale for inhibition of IGF-1R and downstream signaling pathways by NT157 as a novel targeted therapy alone or combined with sorafenib in HCC.

scholarly journals CASK Silence Overcomes Sorafenib Resistance of Hepatocellular Carcinoma Through Activating Apoptosis and Autophagic Cell Death

2021 ◽  
Vol 11 ◽  
Author(s):  
Bisha Ding ◽  
Chang Bao ◽  
Luqi Jin ◽  
Liang Xu ◽  
Weimin Fan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Autophagic Cell Death ◽  
Cell Counting ◽  
Tumor Xenograft ◽  
Confocal Laser ◽  
Loss Of Function ◽  
Jnk Pathway ◽  
Interfering Rna

Hepatocellular carcinoma (HCC) patients usually fail to be treated because of drug resistance, including sorafenib. In this study, the effects of CASK in HCC were investigated using gain- or loss-of-function strategies by performing cell counting kit-8 assay, colony formation assay, flow cytometry, transmission electron microscopy, immunofluorescent confocal laser microscopy, tumor xenograft experiment and immunohistochemistry staining. The current results suggested that CASK expression was positively associated with sorafenib resistance and poor prognosis of HCC. Moreover, inhibition of CASK increased the role of sorafenib partially by promoting apoptosis and autophagy, while CASK overexpression presented the opposite effects. Besides, when treatment with sorafenib, inhibition of apoptosis using the pan-caspase inhibitor Z-VAD-FMK and inhibition of autophagy using autophagy inhibitor 3-Methyladenine (3-MA) or small interfering RNA (siRNA) of LC3B all significantly reversed CASK knockout-induced effects, suggesting that both apoptosis and autophagy were involved in CASK-mediated above functions and autophagy played a pro-death role in this research. Intriguingly, similar results were observed in vivo. In molecular level, CASK knockout activated the c-Jun N-terminal kinase (JNK) pathway, and treatment with JNK inhibitor SP600125 or transiently transfected with siRNA targeting JNK significantly attenuated CASK knockout-mediated autophagic cell death. Collectively, all these results together indicated that CASK might be a promising biomarker and a potential therapeutic target for HCC patients.

scholarly journals The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hiroaki Kanzaki ◽  
Tetsuhiro Chiba ◽  
Junjie Ao ◽  
Keisuke Koroki ◽  
Kengo Kanayama ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Progression Free Survival ◽  
Erk Signaling ◽  
Enzyme Linked Immunosorbent Assay ◽  
Antitumor Effects ◽  
The Impact

AbstractFGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19high (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19low (n = 105) patients, there were no significant differences between FGF19high (n = 21) and FGF19low (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.

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