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Targeting BRAFV600E in thyroid carcinoma: therapeutic implications.

Abstract
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.
AuthorsConstantine S Mitsiades, Joseph Negri, Ciaran McMullan, Douglas W McMillin, Elias Sozopoulos, Galinos Fanourakis, Gerassimos Voutsinas, Sophia Tseleni-Balafouta, Vassiliki Poulaki, David Batt, Nicholas Mitsiades
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 6 Issue 3 Pg. 1070-8 (Mar 2007) ISSN: 1535-7163 [Print] United States
PMID17363500 (Publication Type: Journal Article)
Chemical References
  • AAL 881
  • Isoquinolines
  • RNA, Messenger
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinases
Topics
  • Adenocarcinoma, Follicular (genetics, pathology, prevention & control)
  • Adult
  • Aged
  • Apoptosis (drug effects)
  • Carcinoma (genetics, pathology, prevention & control)
  • Carcinoma, Papillary (genetics, pathology, prevention & control)
  • Carcinoma, Squamous Cell (genetics, pathology, prevention & control)
  • Cell Proliferation (drug effects)
  • Extracellular Signal-Regulated MAP Kinases (metabolism)
  • Female
  • Humans
  • Isoquinolines (pharmacology)
  • Male
  • Middle Aged
  • Mitogen-Activated Protein Kinases (metabolism)
  • Mutation (genetics)
  • Phosphorylation (drug effects)
  • Proto-Oncogene Proteins B-raf (genetics)
  • RNA, Messenger (genetics, metabolism)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction (drug effects)
  • Thyroid Neoplasms (genetics, pathology, prevention & control)
  • Tumor Cells, Cultured (drug effects)

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