-
Signal Transduction and Targeted Therapy Jun 2020Sorafenib is a multikinase inhibitor capable of facilitating apoptosis, mitigating angiogenesis and suppressing tumor cell proliferation. In late-stage hepatocellular... (Review)
Review
Sorafenib is a multikinase inhibitor capable of facilitating apoptosis, mitigating angiogenesis and suppressing tumor cell proliferation. In late-stage hepatocellular carcinoma (HCC), sorafenib is currently an effective first-line therapy. Unfortunately, the development of drug resistance to sorafenib is becoming increasingly common. This study aims to identify factors contributing to resistance and ways to mitigate resistance. Recent studies have shown that epigenetics, transport processes, regulated cell death, and the tumor microenvironment are involved in the development of sorafenib resistance in HCC and subsequent HCC progression. This study summarizes discoveries achieved recently in terms of the principles of sorafenib resistance and outlines approaches suitable for improving therapeutic outcomes for HCC patients.
Topics: Apoptosis; Carcinoma, Hepatocellular; Cell Proliferation; Drug Resistance, Neoplasm; Humans; Liver Neoplasms; Sorafenib; Tumor Microenvironment
PubMed: 32532960
DOI: 10.1038/s41392-020-0187-x -
EBioMedicine Jan 2020In most cases, sorafenib-resistant HCC cells exhibit significant mesenchymal phenotype and stemness features. In this context, tumor cells might undergo cell fate... (Review)
Review
In most cases, sorafenib-resistant HCC cells exhibit significant mesenchymal phenotype and stemness features. In this context, tumor cells might undergo cell fate transition in response to sorafenib or other targeted drugs in the presence or absence of genetic mutations. Therefore, understanding the major characteristics of drug-resistant cells state helps to discover new treatments that overcome drug resistance. To note, little is known about the metabolic or microenvironmental aspects of the certain tumor cell states beyond the genome. This review mainly focuses on the underlying mechanisms of acquired sorafenib resistance based on CSCs and EMT models, which explain tumor heterogeneity and have been considered the major cause of secondary sorafenib resistance. In particular, it discusses how the tumor microenvironment and tumor metabolism regulate cell stemness, mesenchymal state, and sorafenib resistance through epigenetic regulations, and provides reliable targets that might have synergetic effect with sorafenib.
Topics: Carcinoma, Hepatocellular; Drug Resistance, Neoplasm; Epigenesis, Genetic; Humans; Liver Neoplasms; Sorafenib; Tumor Microenvironment
PubMed: 31918403
DOI: 10.1016/j.ebiom.2019.102610 -
The New England Journal of Medicine Dec 2018Desmoid tumors (also referred to as aggressive fibromatosis) are connective tissue neoplasms that can arise in any anatomical location and infiltrate the mesentery,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Desmoid tumors (also referred to as aggressive fibromatosis) are connective tissue neoplasms that can arise in any anatomical location and infiltrate the mesentery, neurovascular structures, and visceral organs. There is no standard of care.
METHODS
In this double-blind, phase 3 trial, we randomly assigned 87 patients with progressive, symptomatic, or recurrent desmoid tumors to receive either sorafenib (400-mg tablet once daily) or matching placebo. Crossover to the sorafenib group was permitted for patients in the placebo group who had disease progression. The primary end point was investigator-assessed progression-free survival; rates of objective response and adverse events were also evaluated.
RESULTS
With a median follow-up of 27.2 months, the 2-year progression-free survival rate was 81% (95% confidence interval [CI], 69 to 96) in the sorafenib group and 36% (95% CI, 22 to 57) in the placebo group (hazard ratio for progression or death, 0.13; 95% CI, 0.05 to 0.31; P<0.001). Before crossover, the objective response rate was 33% (95% CI, 20 to 48) in the sorafenib group and 20% (95% CI, 8 to 38) in the placebo group. The median time to an objective response among patients who had a response was 9.6 months (interquartile range, 6.6 to 16.7) in the sorafenib group and 13.3 months (interquartile range, 11.2 to 31.1) in the placebo group. The objective responses are ongoing. Among patients who received sorafenib, the most frequently reported adverse events were grade 1 or 2 events of rash (73%), fatigue (67%), hypertension (55%), and diarrhea (51%).
CONCLUSIONS
Among patients with progressive, refractory, or symptomatic desmoid tumors, sorafenib significantly prolonged progression-free survival and induced durable responses. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT02066181 .).
Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Double-Blind Method; Female; Fibromatosis, Aggressive; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Progression-Free Survival; Sorafenib; Survival Rate; Young Adult
PubMed: 30575484
DOI: 10.1056/NEJMoa1805052 -
Redox Biology Feb 2023Sorafenib, a tyrosine kinase inhibitor, has an important antitumor effect as a ferroptosis inducer in multiple cancers, including gastric cancer (GC). However, the...
Sorafenib, a tyrosine kinase inhibitor, has an important antitumor effect as a ferroptosis inducer in multiple cancers, including gastric cancer (GC). However, the status of sorafenib as a ferroptosis inducer has recently been questioned. There is very limited information about the relationship between ferroptosis and ATF2, and the role of ATF2 in sorafenib-induced ferroptosis has not been studied. In this study, we investigated the role and underlying molecular mechanisms of ATF2 in sorafenib-induced ferroptosis in GC. We found that ATF2 was significantly upregulated in GC tissues and predicted a poor clinical prognosis. Silencing ATF2 significantly inhibited the malignant phenotype of GC cells. In addition, we observed that ATF2 was activated during sorafenib-induced ferroptosis in GC cells. ATF2 knockdown promoted sorafenib-induced ferroptosis, while ATF2 overexpression showed the opposite results in GC cells. Using ChIP-Seq and RNA-Seq, we identified HSPH1 as a target of ATF2 and further validated it by ChIP‒qPCR analysis. HSPH1 can interact with SLC7A11 (cystine/glutamate transporter) and increase its protein stability. Importantly, knockdown of HSPH1 partly reversed the effects caused by ATF2 overexpression on sorafenib-induced ferroptosis in GC cells. In addition, the results from the tumor xenograft model showed that ATF2 knockdown can effectively enhance sorafenib sensitivity in vivo. Collectively, our study reveals a novel mechanism by which sorafenib induces ferroptosis in GC.
Topics: Animals; Humans; Sorafenib; Ferroptosis; Stomach Neoplasms; Disease Models, Animal; Phenotype; Cell Line, Tumor; Activating Transcription Factor 2
PubMed: 36473315
DOI: 10.1016/j.redox.2022.102564 -
Cell Metabolism May 2020Nonalcoholic steatohepatitis (NASH) is becoming one of the leading causes of hepatocellular carcinoma (HCC). Sorafenib is the only first-line therapy for advanced HCC...
Nonalcoholic steatohepatitis (NASH) is becoming one of the leading causes of hepatocellular carcinoma (HCC). Sorafenib is the only first-line therapy for advanced HCC despite its serious adverse effects. Here, we report that at an equivalent of approximately one-tenth the clinical dose for HCC, sorafenib treatment effectively prevents the progression of NASH in both mice and monkeys without any observed significant adverse events. Mechanistically, sorafenib's benefit in NASH is independent of its canonical kinase targets in HCC, but involves the induction of mild mitochondrial uncoupling and subsequent activation of AMP-activated protein kinase (AMPK). Collectively, our findings demonstrate a previously unappreciated therapeutic effect and signaling mechanism of low-dose sorafenib treatment in NASH. We envision that this new therapeutic strategy for NASH has the potential to translate into a beneficial anti-NASH therapy with fewer adverse events than is observed in the drug's current use in HCC.
Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line; Dose-Response Relationship, Drug; Humans; Liver Neoplasms; Male; Mice; Mice, Inbred C57BL; Mitochondria; Non-alcoholic Fatty Liver Disease; Sorafenib
PubMed: 32375062
DOI: 10.1016/j.cmet.2020.04.011 -
Acta Pharmacologica Sinica Feb 2021Sorafenib is the first-line medication for advanced hepatocellular carcinoma (HCC), but it can only extend limited survival. It is imperative to find a combination...
Sorafenib is the first-line medication for advanced hepatocellular carcinoma (HCC), but it can only extend limited survival. It is imperative to find a combination strategy to increase sorafenib efficacy. Artesunate is such a preferred candidate, because artesunate is clinically well-tolerated and more importantly both drugs can induce ferroptosis through different mechanisms. In this study we investigated the combined effect of sorafenib and artesunate in inducing ferroptosis of HCC and elucidated the involved molecular mechanisms. We showed that artesunate greatly enhanced the anticancer effects of low dose of sorafenib against Huh7, SNU-449, and SNU-182 HCC cell lines in vitro and against Huh7 cell xenograft model in Balb/c nude mice. The combination index method confirmed that the combined effect of sorafenib and artesunate was synergistic. Compared with the treatment with artesunate or sorafenib alone, combined treatment induced significantly exacerbated lipid peroxidation and ferroptosis, which was blocked by N-acetyl cysteine and ferroptosis inhibitors liproxstatin-1 and deferoxamine mesylate, but not by inhibitors of other types of cell death (z-VAD, necrostatin-1 and belnacasan). In Huh7 cells, we demonstrated that the combined treatment induced oxidative stress and lysosome-mediated ferritinophagy, two essential aspects of ferroptosis. Sorafenib at low dose mainly caused oxidative stress through mitochondrial impairments and SLC7A11-invovled glutathione depletion. Artesunate-induced lysosome activation synergized with sorafenib-mediated pro-oxidative effects by promoting sequential reactions including lysosomal cathepsin B/L activation, ferritin degradation, lipid peroxidation, and consequent ferroptosis. Taken together, artesunate could be repurposed to sensitize sorafenib in HCC treatment. The combined treatment can be easily translated into clinical applications.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Artesunate; Carcinoma, Hepatocellular; Cell Line, Tumor; Drug Synergism; Ferroptosis; Humans; Lipid Peroxidation; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Oxidative Stress; Sorafenib; Xenograft Model Antitumor Assays
PubMed: 32699265
DOI: 10.1038/s41401-020-0478-3 -
Theranostics 2021Hepatocellular carcinoma (HCC) is the most common type of liver cancer and one of the leading causes of cancer-related death worldwide. Advanced HCC displays strong... (Review)
Review
Hepatocellular carcinoma (HCC) is the most common type of liver cancer and one of the leading causes of cancer-related death worldwide. Advanced HCC displays strong resistance to chemotherapy, and traditional chemotherapy drugs do not achieve satisfactory therapeutic efficacy. Sorafenib is an oral kinase inhibitor that inhibits tumor cell proliferation and angiogenesis and induces cancer cell apoptosis. It also improves the survival rates of patients with advanced liver cancer. However, due to its poor solubility, fast metabolism, and low bioavailability, clinical applications of sorafenib have been substantially restricted. In recent years, various studies have been conducted on the use of nanoparticles to improve drug targeting and therapeutic efficacy in HCC. Moreover, nanoparticles have been extensively explored to improve the therapeutic efficacy of sorafenib, and a variety of nanoparticles, such as polymer, lipid, silica, and metal nanoparticles, have been developed for treating liver cancer. All these new technologies have improved the targeted treatment of HCC by sorafenib and promoted nanomedicines as treatments for HCC. This review provides an overview of hot topics in tumor nanoscience and the latest status of treatments for HCC. It further introduces the current research status of nanoparticle drug delivery systems for treatment of HCC with sorafenib.
Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Drug Delivery Systems; Humans; Liver Neoplasms; Nanoparticles; Sorafenib
PubMed: 33859758
DOI: 10.7150/thno.54822 -
Cancer Communications (London, England) Apr 2023Cancer-associated fibroblasts (CAFs) play an important role in the induction of chemo-resistance. This study aimed to clarify the mechanism underlying CAF-mediated...
BACKGROUND
Cancer-associated fibroblasts (CAFs) play an important role in the induction of chemo-resistance. This study aimed to clarify the mechanism underlying CAF-mediated resistance to two tyrosine kinase inhibitors (TKIs), sorafenib and lenvatinib, and to identify a novel therapeutic target for overcoming TKI resistance in hepatocellular carcinoma (HCC).
METHODS
We performed a systematic integrative analysis of publicly available gene expression datasets and whole-transcriptome sequencing data from 9 pairs of CAFs and para-cancer fibroblasts isolated from human HCC and para-tumor tissues, respectively, to identify key molecules that might induce resistance to TKIs. We then performed in vitro and in vivo experiments to validate selected targets and related mechanisms. The associations of plasma secreted phosphoprotein 1 (SPP1) expression levels before sorafenib/lenvatinib treatment with progression-free survival (PFS) and overall survival (OS) of 54 patients with advanced HCC were evaluated using Kaplan-Meier and Cox regression analysis.
RESULTS
Bioinformatic analysis identified CAF-derived SPP1 as a candidate molecule driving TKI resistance. SPP1 inhibitors reversed CAF-induced TKI resistance in vitro and in vivo. CAF-derived SPP1 activated rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) through the integrin-protein kinase C-alpha (PKCα) signaling pathway and promoted epithelial-to-mesenchymal transition (EMT). A high plasma SPP1 level before TKI treatment was identified as an independent predictor of poor PFS (P = 0.026) and OS (P = 0.047) in patients with advanced HCC after TKI treatment.
CONCLUSIONS
CAF-derived SPP1 enhances TKI resistance in HCC via bypass activation of oncogenic signals and EMT promotion. Its inhibition represents a promising therapeutic strategy against TKI resistance in HCC. Moreover, plasma SPP1 level before TKI treatment represents a potential biomarker for treatment response prediction.
Topics: Humans; Sorafenib; Carcinoma, Hepatocellular; Cancer-Associated Fibroblasts; Phosphatidylinositol 3-Kinases; Osteopontin; Liver Neoplasms
PubMed: 36919193
DOI: 10.1002/cac2.12414 -
Journal of Clinical Oncology : Official... Sep 2021Donafenib, a novel multikinase inhibitor and a deuterated sorafenib derivative, has shown efficacy in phase Ia and Ib hepatocellular carcinoma (HCC) studies. This study... (Randomized Controlled Trial)
Randomized Controlled Trial
Donafenib Versus Sorafenib in First-Line Treatment of Unresectable or Metastatic Hepatocellular Carcinoma: A Randomized, Open-Label, Parallel-Controlled Phase II-III Trial.
PURPOSE
Donafenib, a novel multikinase inhibitor and a deuterated sorafenib derivative, has shown efficacy in phase Ia and Ib hepatocellular carcinoma (HCC) studies. This study compared the efficacy and safety of donafenib versus sorafenib as first-line therapy for advanced HCC.
PATIENTS AND METHODS
This open-label, randomized, parallel-controlled, multicenter phase II-III trial enrolled patients with unresectable or metastatic HCC, a Child-Pugh score ≤ 7, and no prior systemic therapy from 37 sites across China. Patients were randomly assigned (1:1) to receive oral donafenib (0.2 g) or sorafenib (0.4 g) twice daily until intolerable toxicity or disease progression. The primary end point was overall survival (OS), tested for noninferiority and superiority. Efficacy was primarily assessed in the full analysis set (FAS), and safety was assessed in all treated patients.
RESULTS
Between March 21, 2016, and April 16, 2018, 668 patients (intention-to-treat) were randomly assigned to donafenib and sorafenib treatment arms; the FAS included 328 and 331 patients, respectively. Median OS was significantly longer with donafenib than sorafenib treatment (FAS; 12.1 10.3 months; hazard ratio, 0.831; 95% CI, 0.699 to 0.988; = .0245); donafenib also exhibited superior OS outcomes versus sorafenib in the intention-to-treat population. The median progression-free survival was 3.7 3.6 months ( .0570). The objective response rate was 4.6% 2.7% ( = .2448), and the disease control rate was 30.8% 28.7% (FAS; = .5532). Drug-related grade ≥ 3 adverse events occurred in significantly fewer patients receiving donafenib than sorafenib (125 [38%] 165 [50%]; .0018).
CONCLUSION
Donafenib showed superiority over sorafenib in improving OS and has favorable safety and tolerability in Chinese patients with advanced HCC, showing promise as a potential first-line monotherapy for these patients.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Female; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pyridines; Sorafenib
PubMed: 34185551
DOI: 10.1200/JCO.21.00163 -
Journal of Experimental & Clinical... Jan 2022Drug resistance to sorafenib greatly limited the benefits of treatment in patients with hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) participate in the development...
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.
Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Coenzyme A Ligases; Drug Resistance, Neoplasm; Epigenesis, Genetic; Ferroptosis; Humans; Liver Neoplasms; Mice, Inbred NOD; Sorafenib; Mice
PubMed: 34980204
DOI: 10.1186/s13046-021-02208-x