Dual inhibition of Akt and c‐Met as a second‐line therapy following acquired resistance to sorafenib in hepatocellular carcinoma cells

Han, Peng; Li, Hali; Jiang, Xian; Zhai, Bo; Tan, Gang; Zhao, Dan; Qiao, Haiquan; Liu, Bing; Jiang, Hongchi; Sun, Xueying

doi:10.1002/1878-0261.12039

Cited by 61 publications

(70 citation statements)

References 51 publications

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“…Distinct MET-activating mutations are characterized by different metabolic profiles Numerous preclinical studies and clinical trials are evaluating MET as a potential therapeutic target [16,17]. Detailed understanding of less documented aspects of MET targeting, such as impact on cellular metabolism or immune response, will become particularly important for their successful clinical use.…”

Section: Resultsmentioning

confidence: 99%

Metabolomics reveals tepotinib‐related mitochondrial dysfunction in MET‐activating mutations‐driven models

et al. 2019

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Genetic aberrations in the hepatocyte growth factor receptor tyrosine kinase MET induce oncogenic addiction in various types of human cancers, advocating MET as a viable anticancer target. Here, we report that MET signaling plays an important role in conferring a unique metabolic phenotype to cellular models expressing MET‐activating mutated variants that are either sensitive or resistant toward MET small molecule inhibitors. MET phosphorylation downregulated by the specific MET inhibitor tepotinib resulted in markedly decreased viability and increased apoptosis in tepotinib‐sensitive cells. Moreover, prior to the induction of MET inhibition‐dependent cell death, tepotinib also led to an altered metabolic signature, characterized by a prominent reduction of metabolite ions related to amino sugar metabolism, gluconeogenesis, glycine and serine metabolism, and of numerous TCA cycle‐related metabolites such as succinate, malate, and citrate. Functionally, a decrease in oxygen consumption rate, a reduced citrate synthase activity, a drop in membrane potential, and an associated misbalanced mitochondrial function were observed exclusively in MET inhibitor‐sensitive cells. These data imply that interference with metabolic state can be considered an early indicator of efficient MET inhibition and particular changes reported here could be explored in the future as markers of efficacy of anti‐MET therapies.

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Section: Resultsmentioning

confidence: 99%

Metabolomics reveals tepotinib‐related mitochondrial dysfunction in MET‐activating mutations‐driven models

et al. 2019

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“…Han et al . also reported HGF overexpression and enhanced MET activation in sorafenib‐resistant HCC cells. Thus, in the present study, we focused on sorafenib resistance induced by HGF.…”

Section: Discussionmentioning

confidence: 74%

Regorafenib reverses HGF‐induced sorafenib resistance by inhibiting epithelial‐mesenchymal transition in hepatocellular carcinoma

et al. 2019

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Sorafenib resistance is one of the major obstacles towards achieving a better outcome in patients with advanced hepatocellular carcinoma (HCC), in which aberrant activation of the hepatocyte growth factor (HGF)/mesenchymal‐epithelial transition pathway is frequently observed. Here, we report that HCC cells develop sorafenib resistance following HGF stimulation. Furthermore, HGF activates the downstream extracellular signal‐related kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) pathway and induces epithelial–mesenchymal transition (EMT) by up‐regulating Snail in HCC cells. Inhibition of ERK and STAT3 abolished the rescue effect of HGF by down‐regulating Snail and EMT. Moreover, phosphoinositide 3‐kinase/Akt was also activated in HGF‐treated HCC cells, although it had no effect on Snail expression. Notably, we also found that regorafenib reversed HGF‐induced sorafenib resistance by inhibiting ERK and STAT3, and subsequently down‐regulating Snail and EMT. Taken together, our results indicate that HGF induces sorafenib resistance by activating phosporylated (P)‐ERK/Snail/EMT and P‐STAT3/Snail/EMT pathways. Inhibition of P‐ERK and P‐STAT3 by regorafenib can block HGF‐induced EMT, thereby reversing HGF‐induced sorafenib resistance.

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“…Exposure to CDDP leads to the higher expression of p-PEA-15 and p-AKT, contributing to the mechanisms of CDDP resistance. Activated AKT regulates GSK-3β, which controls cell apoptosis and proliferation by regulating p27, cyclin D1 and caspase-9 (23,36). Activated AKT is also able to mediate cell proliferation and apoptosis by regulating the PEA-15 pathway.…”

Section: Discussionmentioning

confidence: 99%

PEA‑15 contributes to the clinicopathology and AKT‑regulated cisplatin resistance in gastric cancer

Jiang

Zhang

et al. 2018

Oncol Rep

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Phosphoprotein enriched in astrocytes 15 (PEA-15) plays an important role in controlling biological behaviors of cancer cells. In the present study, we demonstrated that PEA-15 was overexpressed in gastric cancer tissues and associated with tumor staging, differentiation, pathological types and the prognosis of patients. Gastric cancer cells expressed variable levels of PEA-15 and its bi-phosphorylation forms, p-PEA-15 (Ser104) and p-PEA-15 (Ser116). To gain insight into the functional role of PEA-15, we generated cells stably depleted of PEA-15 and resistant to cisplatin (CDDP) from human gastric cancer cells. PEA-15 depletion inhibited cell proliferation by reducing cyclin D1 expression through the extracellular signal-regulated kinase (ERK) pathway, resulting in cell cycle arrest at the G1 phase, and induced apoptosis by activating caspase-8. PEA-15 depletion also enhanced the inhibitory effect of CDDP that caused cell cycle arrest at the S phase and also enhanced the pro-apoptotic activity of CDDP in vitro and in animal models of tumorigenesis and therapeutic effects. PEA-15 and its phosphorylated forms were overexpressed in CDDP-resistant cells, which had higher levels of p-AKT. Specific inhibition of AKT by MK2206 reduced the expression of p-PEA-15 at the Ser116 residue, resulting in sequential downregulation of p-ERK1/2, cyclin D1 and caspase-8 activation. However, depletion of PEA-15 had little effect on AKT expression or phosphorylation, or its downstream factors including p27, glycogen synthase kinase 3β and caspase-9, indicating that the regulatory effects between PEA-15 and AKT were unidirectional. In summary, the results indicated that PEA-15 expression was associated with clinicopathology and prognosis in gastric cancer and was regulated by AKT to participate in CDDP resistance, indicating that it may be a potential target for overcoming CDDP resistance in the treatment of gastric cancer.

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Dual inhibition of Akt and c‐Met as a second‐line therapy following acquired resistance to sorafenib in hepatocellular carcinoma cells

Cited by 61 publications

References 51 publications

Metabolomics reveals tepotinib‐related mitochondrial dysfunction in MET‐activating mutations‐driven models

Metabolomics reveals tepotinib‐related mitochondrial dysfunction in MET‐activating mutations‐driven models

Regorafenib reverses HGF‐induced sorafenib resistance by inhibiting epithelial‐mesenchymal transition in hepatocellular carcinoma

PEA‑15 contributes to the clinicopathology and AKT‑regulated cisplatin resistance in gastric cancer

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