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Model of HER2/HER3-induced primary resistance to MAPK inhibitors in BRAF mutant thyroid cancer cells. RAF or MEK inhibitors release transcription repressor CTBP protein/s from the HER3 promoter and induce HER3 gene expression. Autocrine-secreted NRG-1 binds to HER3, triggers HER3/HER2 heterodimerization and receptor phosphorylation, inducing PI3K and reactivating MAPK signaling, thus promoting resistance to growth inhibition.
