Exogenous HGF Bypasses the Effects of ErbB Inhibition on Tumor Cell Viability in Medulloblastoma Cell Lines.
Recent clinical trials investigating receptor tyrosine kinase (RTK) inhibitors showed a limited clinical response in medulloblastoma. The present study investigated the role of micro-environmental growth factors expressed in the brain, such as HGF and EGF, in relation to the effects of hepatocyte growth factor receptor (MET) and epidermal growth factor receptor family (ErbB1-4) inhibition in medulloblastoma cell lines. Medulloblastoma cell lines were treated with tyrosine kinase inhibitors crizotinib or canertinib, targeting MET and ErbB1-4, respectively. Upon treatment, cells were stimulated with VEGF-A, PDGF-AB, HGF, FGF-2 or EGF. Subsequently, we measured cell viability and expression levels of growth factors and downstream signaling proteins. Addition of HGF or EGF phosphorylated MET or EGFR, respectively, and demonstrated phosphorylation of Akt and ERK1/2 as well as increased tumor cell viability. Crizotinib and canertinib both inhibited cell viability and phosphorylation of Akt and ERK1/2. Specifically targeting MET using shRNA's resulted in decreased cell viability. Interestingly, addition of HGF to canertinib significantly enhanced cell viability as well as phosphorylation of Akt and ERK1/2. The HGF-induced bypass of canertinib was reversed by addition of crizotinib. HGF protein was hardly released by medulloblastoma cells itself. Addition of canertinib did not affect RTK cell surface or growth factor expression levels. This manuscript points to the bypassing capacity of exogenous HGF in medulloblastoma cell lines. It might be of great interest to anticipate on these results in developing novel clinical trials with a combination of MET and EGFR inhibitors in medulloblastoma.
Department of Pediatric Oncology/Hematology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands.
Walderik W
WW
Zomerman
Department of Pediatric Oncology/Hematology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
Sabine L A
SL
Plasschaert
Department of Pediatric Oncology/Hematology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands.
Sander H
SH
Diks
Department of Pediatric Oncology/Hematology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands.
Harm-Jan
HJ
Lourens
Department of Pediatric Oncology/Hematology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands.
Tiny
T
Meeuwsen-de Boer
Department of Neurosurgery, University Medical Center Groningen, Groningen, The Netherlands.
Eelco W
EW
Hoving
Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, The Netherlands.
Wilfred F A
WF
den Dunnen
Department of Pediatric Oncology/Hematology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands.
Eveline S J M
ES
de Bont
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm; D004815:Epidermal Growth Factor / Q000502:physiology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D008527:Medulloblastoma; D009025:Morpholines / Q000494:pharmacology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction
D000970:Antineoplastic Agents; C066855:HGF protein, human; D009025:Morpholines; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; C420268:Canertinib; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met