The dual axis of tumorigenesis: MAPK and PI3K/AKT pathways in papillary thyroid carcinoma

The MAPK and PI3K/AKT pathways are important components in cell growth and proliferation, which, when activated, result in cancer formation. Molecular alterations are the main cause of activation of the MAPK and PI3K/AKT pathways in the development of papillary thyroid carcinoma (PTC), the most common endocrine cancer. Activation of the MAPK pathway is usually caused by mutations in the BRAF, RAS, RET/PTC, and NTRK genes, while the activation of the PI3K/AKT pathway results from alterations in the PIK3CA, PTEN, and AKT genes. Moreover, hyperactivation of the MAPK pathway can be caused by overexpression of RTKs, GPCRs, and mutation in PTEN. Interactions between the two signaling pathways exacerbate tumor aggressiveness, dedifferentiation, radioiodine resistance, and response to targeted therapy in PTC. Recent developments in personalized medicine, including the introduction of new molecular diagnostic tools and targeted agents, have made considerable progress in the risk stratification and treatment strategies for papillary thyroid carcinoma. The current article reviews molecular mechanisms of activation of MAPK and PI3K/AKT pathways, their interaction, clinicopathological importance, and targeted treatments in papillary thyroid carcinoma.