fig6

Figure 6. Thyroid cancer oncogenesis frequently invokes activation of PI3K-Akt-mTOR signaling in FTC and ATC and MAPK signaling in PTC and ATC. PI3K signaling is often induced by PI3K activating mutations and copy number variations in Akt and RTKs. The PI3K pathway induces changes in cell metabolism by regulating glycogen storage via Akt, protein synthesis and autophagy via mTORC1, and fatty acid metabolism from Akt and mTORC1, which is regulated by AMPK. BRAF is often constitutively activated in PTC and ATC tumors via the V600E gain-of-function mutation which is correlated with high expression of enzymes in serine synthesis. Downstream of BRAF is ERK, which phosphorylates pyruvate kinase 2 (PKM2) to promote nucleotide synthesis and ERK phosphorylation. Aggressive TCs such as ATC often harbor Ras mutations that activate both sets of pathways. PI3K and MAPK signaling increases expression and stability of the transcription factors hypoxia-inducible factor 1 alpha (HIF1A) and MYC, which in turn increase expression of enzymes in glycolysis, PPP, and amino acid metabolism to promote the Warburg effect. Kinase inhibitors marked in bold have demonstrated varying levels of success in aggressive TC, but drug resistance and tumor recurrence often develop, suggesting the need for combined therapies.