Targeting BRAFV600E in thyroid carcinoma: therapeutic implications.
B-Raf is an important mediator of cell proliferation and survival signals transduced via the Ras-Raf-MEK-ERK cascade. BRAF mutations have been detected in several tumors, including papillary thyroid carcinoma, but the precise role of B-Raf as a therapeutic target for thyroid carcinoma is still under investigation. We analyzed a panel of 93 specimens and 14 thyroid carcinoma cell lines for the presence of BRAF mutations and activation of the mitogen-activated protein/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. We also compared the effect of a B-Raf small inhibitory RNA construct and the B-Raf kinase inhibitor AAL881 on both B-Raf wild-type and mutant thyroid carcinoma cell lines. We found a high prevalence of the T1799A (V600E) mutation in papillary and anaplastic carcinoma specimens and cell lines. There was no difference in patient age, B-Raf expression, Ki67 immunostaining, or clinical stage at presentation between wild-type and BRAF(V600E) specimens. Immunodetection of phosphorylated and total forms of MEK and ERK revealed no difference in their phosphorylation between wild-type and BRAF(V600E) patient specimens or cell lines. Furthermore, a small inhibitory RNA construct targeting the expression of both wild-type B-Raf and B-Raf(V600E) induced a comparable reduction of viability in both wild-type and BRAF(V600E) mutant cancer cells. Interestingly, AAL881 inhibited MEK and ERK phosphorylation and induced apoptosis preferentially in BRAF(V600E)-harboring cells than wild-type ones, possibly because of better inhibitory activity against B-Raf(V600E). We conclude that B-Raf is important for the pathophysiology of thyroid carcinomas irrespective of mutational status. Small molecule inhibitors that selectively target B-Raf(V600E) may provide clinical benefit for patients with thyroid cancer.
Mitsiades
Constantine S
CS
Department of Medical Oncology, Dana-Farber Cancer Institute, Mayer Building, Room M555, 44 Binney Street, Boston, MA 02115, USA. Constantine_Mitsiades@dfci.harvard.edu
Negri
Joseph
J
McMullan
Ciaran
C
McMillin
Douglas W
DW
Sozopoulos
Elias
E
Fanourakis
Galinos
G
Voutsinas
Gerassimos
G
Tseleni-Balafouta
Sophia
S
Poulaki
Vassiliki
V
Batt
David
D
Mitsiades
Nicholas
N
D018263:Adenocarcinoma, Follicular / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D014407:Tumor Cells, Cultured / Q000187:drug effects
C514876:AAL 881; D007546:Isoquinolines; D012333:RNA, Messenger; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases