title: BRaf and MEK inhibitors differentially regulate cell fate and microenvironment in human hepatocellular carcinoma.
abstract: OBJECTIVE
  Small molecule inhibitors of the mitogen-activated protein kinase (MAPK) pathway, such as sorafenib, represent novel treatment options for advanced hepatocellular carcinoma. The aim of our study was to identify downstream targets as biomarker candidates that are directly linked to the oncogenic MAPK pathway in hepatocellular carcinoma and correlate with inhibition of this pathway by multikinase inhibitors.
  
  
  METHODS
  Hepatocellular carcinoma cell lines and fresh tumor and tumor-free liver tissues from patients with hepatocellular carcinoma were incubated with different BRaf or MEK inhibitors and analyzed for kinase phosphorylation, proliferation, induction of apoptosis, and chemokine secretion.
  
  
  RESULTS
  Hepatocellular carcinoma cell lines responded differentially to these inhibitors in a dose-dependent manner, even those targeting the same kinase. Sorafenib inhibited both MEK1 and ERK1/2 phosphorylation at high but increased signaling at low concentrations. Similarly, PLX4720 increased MEK/ERK signaling independently from mutations in BRaf or NRas. MEK inhibitors decreased ERK1/2 phosphorylation in a dose-dependent manner. These signaling characteristics correlated with inhibition of proliferation, induction of apoptosis, and chemokine secretion. Fresh tissues derived from patients diagnosed with primary hepatocellular carcinoma responded to these inhibitors with changes in their microenvironment following the patterns observed in hepatocellular carcinoma cells.
  
  
  CONCLUSIONS
  Oncogenic signaling of the MAPK pathway influences hepatocellular carcinoma sensitivity to treatment with BRaf and MEK inhibitors about cell fate independently from mutations in BRaf and NRas. MAPK inhibitors have a strong impact on chemokine secretion as a consequence of interference with oncogenic signaling. Therefore, novel biomarker candidates associated with the hepatocellular carcinoma microenvironment may be developed for prediction and monitoring of treatment response to small molecule inhibitors.
authors.affiliation: Authors' Affiliations: Division of Molecular Genome Analysis B050, German Cancer Research Center (DKFZ); Immunomonitoring Unit, National Center for Tumor Diseases (NCT) at the DKFZ; Department of Translational Immunology, DKFZ and NCT; Department of General, Visceral and Transplantation Surgery, University Hospital, Heidelberg; Institute of Transplant Immunology, OE8889, IFB-Tx; Departments of Gastroenterology, Hepatology and Endocrinology; and Abdominal and Transplantation Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Breunig
authors.forename: Bernadett J
authors.initials: BJ
authors.lastname: Mueller
authors.forename: Ludmila
authors.initials: L
authors.lastname: Umansky
authors.forename: Kristin
authors.initials: K
authors.lastname: Wahl
authors.forename: Katrin
authors.initials: K
authors.lastname: Hoffmann
authors.forename: Frank
authors.initials: F
authors.lastname: Lehner
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Heike
authors.initials: H
authors.lastname: Bantel
authors.forename: Christine S
authors.initials: CS
authors.lastname: Falk
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D060833:Cellular Microenvironment / Q000187:drug effects*; D018925:Chemokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009362:Neoplasm Metastasis; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D018925:Chemokines; D036341:Intercellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases