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Cancer Therapy: Preclinical |
Authors' Affiliations: 1 Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, Cincinnati, Ohio and 2 Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts
Requests for reprints: James A. Fagin, Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, 3125 Eden Avenue, Cincinnati, OH 45267-0547. Phone: 513-558-4444; Fax: 513-558-8581; E-mail: james.fagin{at}uc.edu.
Purpose: Papillary thyroid carcinomas are associated with nonoverlapping activating mutations of RET, NTRK, RAS and BRAF, which altogether are present in 
70% of cases. We postulated that compounds that inhibit a distal effector in the mitogen-activated protein kinase (MAPK) pathway would inhibit growth and tumorigenicity of human thyroid cancer cell lines with mutations of RET or BRAF.
Experimental Design and Results: We first examined the effects of AAL-881 and LBT-613, two inhibitors of RAF kinase activity, on RAF-MAPK/extracellular signal–regulated kinase (ERK) kinase (MEK)-ERK activation in thyroid PCCL3 cells after conditional induction of expression of H-RASG12V or BRAFV600E. Both compounds blocked RAS and RAF-dependent MEK and ERK phosphorylation. They also potently blocked MEK phosphorylation in human thyroid cancer cell lines with either RET/PTC1 (TPC1) or BRAFV600E (NPA, ARO, and FRO) mutations. Inhibition of ERK phosphorylation was transient in TPC1 and ARO cells, with recovery of ERK phosphorylation associated with concomitant down-regulation of the MAPK phosphatases MKP-3 and DUSP5. Both compounds inhibited growth of all cell lines, with LBT-613 being 10-fold more potent than AAL-881. TPC1 cells were more sensitive to growth inhibition (IC50 0.1-0.25 and 0.05 µmol/L for AAL-881 and LBT-613, respectively) than BRAF (+) lines (IC50 2.5-5 and 0.1-0.5 µmol/L, respectively). Growth inhibition was associated with G1 arrest, and induction of cell death. Growth of ARO and NPA tumor xenografts was inhibited by LBT-613 or AAL-881. MEK and ERK phosphorylation was inhibited by both compounds in ARO but not in NPA cell xenografts.
Conclusions: Compounds that inhibit kinase activity are effective growth inhibitors for poorly differentiated thyroid cancer cell lines with either RET or RAF mutations, and hold promise for treatment of most forms of papillary thyroid carcinoma.
Commentary
Clin. Cancer Res. 2006 12: 1661-1664.
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