JOURNAL ARTICLE

Activation of the RAS/RAF/ERK signaling pathway contributes to resistance to sunitinib in thyroid carcinoma cell lines

Annamaria Piscazzi, Eleonora Costantino, Francesca Maddalena, Maria Iole Natalicchio, Assunta Maria Teresa Gerardi, Raffaele Antonetti, Mauro Cignarelli, Matteo Landriscina
Journal of Clinical Endocrinology and Metabolism 2012, 97 (6): E898-906
22442268

CONTEXT: Sunitinib is currently being evaluated in advanced human thyroid carcinomas, based on the rationale that the vascular endothelial growth factor and platelet-derived growth factor receptors and the RET/PTC rearrangement are valuable targets for the treatment of this malignancy. However, criteria for selecting thyroid tumors that may benefit from sunitinib are lacking.

DESIGN: The effect of activating somatic mutations in the KRAS and BRAF genes on the responsiveness to sunitinib was evaluated in a panel of thyroid cancer cell lines harboring wild-type KRAS and BRAF genes, the RET/PTC1 rearrangement, the G12R KRAS, or the V600E BRAF mutation.

RESULTS: Sunitinib was found to selectively inhibit cell proliferation, induce cell accumulation in the G0-G1 phase, and inhibit the phosphorylation of ERK1/2 in both KRAS/BRAF wild-type thyroid cancer cells and in tumor cells harboring the RET/PTC rearrangement, whereas it was completely ineffective in KRAS- or BRAF-mutated thyroid carcinoma cells. This differential antitumor activity of sunitinib did not correlate with the expression profile of the vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor-α and cKIT genes. Of note, the constitutive activation of RAS/RAF/ERK signaling in KRAS/BRAF wild-type cells by transfection of the R12 HRAS or V600E BRAF mutants or stimulation with epithelial growth factor resulted in the loss of responsiveness to sunitinib, whereas pharmacological inhibition of MAPK kinase activity resulted in the resensitization of KRAS- or BRAF-mutated cells to the multikinase inhibitor.

CONCLUSIONS: The constitutive activation of the RAS/RAF/ERK pathway may favor resistance to sunitinib in thyroid carcinoma cells.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read
22442268
×

Save your favorite articles in one place with a free QxMD account.

×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"