Sorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity

Cabral, Loraine Kay; Tiribelli, Claudio; Sukowati, Caecilia

doi:10.3390/cancers12061576

Cited by 118 publications

(79 citation statements)

References 127 publications

(143 reference statements)

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“…As an inhibitor targeting multiple tyrosine protein kinases (VEGFR, PDGFR and Raf family kinases), sorafenib acts on numerous targets to inhibit cancer proliferation and tumor angiogenesis, which can effectively lead to a decrease in mortality in HCC patients. 18 , 19 Advanced stage HCC patients can benefit from 400mg twice daily sorafenib therapy. 5 , 6 , 20 To date, however, clinical trials have revealed that only about 30% patients show sensitivity to sorafenib, and HCC usually progresses within 6 months resulting from resistance to sorafenib.…”

Section: Discussionmentioning

confidence: 99%

AG-1024 Sensitizes Sorafenib-Resistant Hepatocellular Carcinoma Cells to Sorafenib via Enhancing G1/S Arrest

Zhou

Lou

Chen

et al. 2021

OTT

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Purpose The frequency in resistance to sorafenib accounts for the grim prognosis of advanced hepatocellular carcinoma (HCC). In the present study, we explore the anti-cancer efficacy of co-administration of sub-toxic AG-1024 with sorafenib in HCC cells to enhance the sensitivity of these cells to sorafenib. Materials and Methods Two acquired sorafenib-resistant HCC cells, SNU-sora-5 and SK-sora-5, were established and verified. The MTT assay, colony formation assay, cell morphology detection and flow cytometric analysis were then used to determine the anti-tumor effects of the co-administration of sub-toxic AG-1024 and sorafenib. Finally, the potential molecular mechanism was preliminarily examined. Results Compared to parental cell lines, the acquired sorafenib-resistant cell lines, SNU-sora-5 and SK-sora-5, were more resistant to sorafenib. Sub-toxic AG-1024 markedly enhanced sorafenib-mediated cell inhibition in acquired sorafenib-resistant HCC strains, with a reversal index (RI) of 4.64 in SNU-sora-5 and 4.58 in SK-sora-5 cell lines. Moreover, co-administration of sub-toxic AG-1024 and sorafenib exerted dramatic cytotoxicity compared with sorafenib alone in the intrinsic sorafenib-resistant HCC-LM3 cells. In contrast to high-dose sorafenib, sub-toxic AG-1024 combined with sorafenib had less impact on apoptosis while significantly enhancing G1/S arrest via activation of the mTOR/p21 signaling pathway. The more, pharmacological inhibition of mTOR activity by inhibitor Palomid 529 significantly antagonized the synergistic anti-cancer effects of AG-1024 and sorafenib in HCC cells. Conclusion The current findings indicate that sub-toxic AG-1024 may be a promising therapeutic agent in enhancing the sensitivity in HCC cells to sorafenib, bringing hope to HCC patients refractory to sorafenib treatment.

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Section: Discussionmentioning

confidence: 99%

AG-1024 Sensitizes Sorafenib-Resistant Hepatocellular Carcinoma Cells to Sorafenib via Enhancing G1/S Arrest

Zhou

Lou

Chen

et al. 2021

OTT

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“…Like most tumors, HCC tumors show heterogeneity [25,26]. After the multiple stages of cell division and proliferation during tumor development, tumor cells undergo various genetic changes, resulting in aberrant growth rate, invasion ability, sensitivity to drugs, and other activities [27].…”

Section: Discussionmentioning

confidence: 99%

TP53 Mutation in Circulating exoDNA Correlates with Outcomes of Patients with Hepatocellular Carcinoma.

Lei

et al. 2020

Preprint

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Background: Detection of tumor-specific mutations in exosomal DNA (exoDNA), a promising liquid biopsy material, has been used to assess the prognosis of hepatocellular carcinoma (HCC) patients. This study was the first to use a droplet digital PCR (ddPCR) platform to detect tumor-specific mutations in circulating exoDNA and to evaluate the prognosis of HCC patients.Methods: Blood samples from 40 HCC patients were obtained between 2018 and 2019, with clinically annotated follow-up until 2020. A ddPCR platform was used to detect an HCC tumor-specific mutation in the TP53 gene. We analyzed the correlation between TP53 mutation detected in circulating exoDNA and patient clinical data. The ratio of mutant droplets/total droplets (MD/TD) was calculated according to ddPCR results.Results: TP53 mutations in circulating exoDNA were detected in 33 of the 40 patients (82.5%). Patients with high MD/TD (>62.5%) were more likely to show microvascular invasion (P=0.028) and high MD/TD predicted a shorter recurrence-free survival time (P<0.001).Conclusions: High MD/TD of TP53 detected in serum was associated with microvascular invasion and might be used to predict the prognosis of HCC patients. The diagnostic performance of detecting exosome-derived tumor DNA will likely improve when more mutations in other tumor-specific genes are combined.

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“…Possible roles of USP2 in autophagy have also been recently reported. Sorafenib has been used to treat advanced stage hepatocellular carcinoma (HCC) [ 79 ]; however, sorafenib resistance is frequently acquired and is one of the most severe challenges in treating HCC [ 80 ]. A sorafenib-resistant Huh7-derived clone exhibited no obvious activation of caspase-3 and PARP, concomitant with a decreased rate of apoptosis [ 81 ].…”

Section: Apoptosis and Autophagymentioning

confidence: 99%

USP2-Related Cellular Signaling and Consequent Pathophysiological Outcomes

Kitamura

Hashimoto

2021

IJMS

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Ubiquitin specific protease (USP) 2 is a multifunctional deubiquitinating enzyme. USP2 modulates cell cycle progression, and therefore carcinogenesis, via the deubiquitination of cyclins and Aurora-A. Other tumorigenic molecules, including epidermal growth factor and fatty acid synthase, are also targets for USP2. USP2 additionally prevents p53 signaling. On the other hand, USP2 functions as a key component of the CLOCK/BMAL1 complex and participates in rhythmic gene expression in the suprachiasmatic nucleus and liver. USP2 variants influence energy metabolism by controlling hepatic gluconeogenesis, hepatic cholesterol uptake, adipose tissue inflammation, and subsequent systemic insulin sensitivity. USP2 also has the potential to promote surface expression of ion channels in renal and intestinal epithelial cells. In addition to modifying the production of cytokines in immune cells, USP2 also modulates the signaling molecules that are involved in cytokine signaling in the target cells. Usp2 knockout mice exhibit changes in locomotion and male fertility, which suggest roles for USP2 in the central nervous system and male genital tract, respectively. In this review, we summarize the cellular events with USP2 contributions and list the signaling molecules that are upstream or downstream of USP2. Additionally, we describe phenotypic differences found in the in vitro and in vivo experimental models.

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Sorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity

Cited by 118 publications

References 127 publications

AG-1024 Sensitizes Sorafenib-Resistant Hepatocellular Carcinoma Cells to Sorafenib via Enhancing G1/S Arrest

AG-1024 Sensitizes Sorafenib-Resistant Hepatocellular Carcinoma Cells to Sorafenib via Enhancing G1/S Arrest

TP53 Mutation in Circulating exoDNA Correlates with Outcomes of Patients with Hepatocellular Carcinoma.

USP2-Related Cellular Signaling and Consequent Pathophysiological Outcomes

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