title: Inhibition of acquired-resistance hepatocellular carcinoma cell growth by combining sorafenib with phosphoinositide 3-kinase and rat sarcoma inhibitor.
abstract: To provide support for combined usage of phosphoinositide 3-kinase (PI3K) inhibitors or mitogen-activated protein kinase pathway inhibitors together with sorafenib in treatment of sorafenib-resistant hepatocellular carcinoma.
  
  
  
  The sorafenib-resistant cell lines were established to evaluate the effects of MK-2206 2HCL, a dual PI3K/mammalian target of rapamycin (mTOR) inhibitor, and PD0325901, an rat sarcoma (RAS) and/or extracellular signal-regulated kinase (ERK) inhibitor, on cell proliferation and apoptosis, as both single and combined treatments with sorafenib. In addition, multidrug resistance 1 gene expression, mutation status of key members in PI3K/mTOR, and RAS/ERK pathways and pathway activation were analyzed to identify predictors of drug response.
  
  
  
  Molecular studies reveal that combining MK-2206 2HCL or PD0325901 with sorafenib not only has a synergistic effect, in suppressing PI3K/protein kinase B/mTOR and RAS/MEK/ERK signaling more effectively than either treatment alone, but also prevents the cross activation of the other pathway that occurs with single treatments in both sorafenib sensitive and resistant lines. PD0325901 exhibited a stronger synergic effect with sorafenib than MK-2206 2HCL. Sorafenib-resistant cell lines were characterized by activation of both of the two pathways, as indicated by multidrug resistance 1 gene expression profiles and pathway activity analysis.
  
  
  
  Our studies have showed that both inhibitors of PI3K/mTOR and RAS/ERK signaling are potentially effective antihepatocellular carcinoma drugs especially in treating sorafenib-resistant hepatocellular carcinoma.
authors.affiliation: Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
authors.forename: Chang-Hao
authors.initials: CH
authors.lastname: Wu
authors.affiliation: Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China. Electronic address: hongweizhang88@126.com.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D014408:Biomarkers, Tumor; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D010671:Phenylurea Compounds; D009536:Niacinamide; C506614:mirdametinib; D004159:Diphenylamine; D000077157:Sorafenib
keywords: Drug resistance; ERK; Hepatocellular carcinoma; MDR1; PI3K; Sorafenib