Fyn and SRC are effectors of oncogenic epidermal growth factor receptor signaling in glioblastoma patients.
Activating epidermal growth factor receptor (EGFR) mutations are common in many cancers including glioblastoma. However, clinical responses to EGFR inhibitors are infrequent and short-lived. We show that the Src family kinases (SFK) Fyn and Src are effectors of oncogenic EGFR signaling, enhancing invasion and tumor cell survival in vivo. Expression of a constitutively active EGFR mutant, EGFRvIII, resulted in activating phosphorylation and physical association with Src and Fyn, promoting tumor growth and motility. Gene silencing of Fyn and Src limited EGFR- and EGFRvIII-dependent tumor cell motility. The SFK inhibitor dasatinib inhibited invasion, promoted tumor regression, and induced apoptosis in vivo, significantly prolonging survival of an orthotopic glioblastoma model expressing endogenous EGFRvIII. Dasatinib enhanced the efficacy of an anti-EGFR monoclonal antibody (mAb 806) in vivo, further limiting tumor growth and extending survival. Examination of a large cohort of clinical samples showed frequent coactivation of EGFR and SFKs in glioblastoma patients. These results establish a mechanism linking EGFR signaling with Fyn and Src activation to promote tumor progression and invasion in vivo and provide rationale for combined anti-EGFR and anti-SFK targeted therapies.
Lu
Kan V
KV
Department of Pathology and Laboratory Medicine, University of California-Los Angeles David Geffen School of Medicine, USA.
Zhu
Shaojun
S
Cvrljevic
Anna
A
Huang
Tiffany T
TT
Sarkaria
Shawn
S
Ahkavan
David
D
Dang
Julie
J
Dinca
Eduard B
EB
Plaisier
Seema B
SB
Oderberg
Isaac
I
Lee
Yohan
Y
Chen
Zugen
Z
Caldwell
Jeremy S
JS
Xie
Yongmin
Y
Loo
Joseph A
JA
Seligson
David
D
Chakravari
Arnab
A
Lee
Francis Y
FY
Weinmann
Roberto
R
Cloughesy
Timothy F
TF
Nelson
Stanley F
SF
Bergers
Gabriele
G
Graeber
Thomas
T
Furnari
Frank B
FB
James
C David
CD
Cavenee
Webster K
WK
Johns
Terrance G
TG
Mischel
Paul S
PS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016543:Central Nervous System Neoplasms / Q000378:metabolism* / Q000473:pathology; D000069439:Dasatinib; D004357:Drug Synergism; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D009154:Mutation; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; C410723:epidermal growth factor receptor VIII; C518939:monoclonal antibody 806; D066246:ErbB Receptors; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases; D000069439:Dasatinib
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