The most common thyroid malignancy is papillary thyroid cancer (PTC). Mortality rates from PTC mainly depend
on its aggressiveness. Geno- and phenotyping of aggressive PTC has advanced our understanding of treatment failures
and of potential future therapies. Unraveling molecular signaling pathways of PTC including its aggressive forms
will hopefully pave the road to reduce mortality but also morbidity from this cancer. The mitogen-activated protein kinase
and the phosphatidylinositol 3-kinase signaling pathway as well as the family of RAS oncogenes and BRAF as a member
of the RAF protein family and the aberrant expression of microRNAs miR-221, miR-222, and miR-146b all play major
roles in tumor initiation and progression of aggressive PTC. Small molecule tyrosine kinase inhibitors targeting BRAFmediated
events, vascular endothelial growth factor receptors, RET/PTC rearrangements, and other molecular targets,
show promising results to improve treatment of radioiodine resistant, recurrent, and aggressive PTC.
Keywords: BRAF, P13/Akt, Papillary thyroid cancer, Signaling, Tyrosine kinase, VEGF.
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