In radioiodine-resistant, resectable thyroid cancer, inhibition of mitogen-activated protein kinases (MAPK) restored iodine incorporation (redifferentiation) (RR-TC). However, in BRAFV600E-mutant (BRAF-MUT) RR-TC, the outcomes were disappointing. Here researchers evaluated the feasibility and efficacy of redifferentiation therapy in patients with BRAF-MUT or wildtype (BRAF-WT) RR-TC by modulating MAPK according to their genotype. Trametinib (BRAF-WT) or trametinib + dabrafenib (BRAF-MUT) for 21±3 days was given to patients in this prospective single-center, two-arm phase II research 123I-scintigraphy was used to evaluate redifferentiation. Once radioiodine uptake had been recovered, 131I therapy guided by 124I was administered. Redifferentiation rate was the primary measure of success. Treatment response (thyroglobulin, RECIST 1.1) and safety were the secondary goals. Investigators used a receiver operating characteristic analysis and the Youden J statistic to evaluate the parameters that most reliably foretell effective redifferentiation. About 7 out of 20 patients (35%), including 2 of 6 (33% in the BRAF-MUT group and 5 of 14 (36%) in the BRAF-WT group, showed redifferentiation. The median (interquartile range) 131I therapy activity dose given to patients was 300.0 (273.0-421.6) mCi. About 71% (5/7) of patients showed some decrease in thyroglobulin, 14% (1/14) showed no change, while the remaining patients had either stable or progressing disease according to the RECIST 1.1 criteria. (SUVpeak) less than 10 at 2[18F] A positive result on fluoro-2-deoxy-D-glucose (FDG)-PET was linked to redifferentiation (P=0.01). Only 1 patient experienced transient pyrexia (degree 3), and 1 experienced a rash (grade 4). It was shown that around 1/3rd of patients in each group experienced effective redifferentiation after receiving genotype-guided MAPK inhibition. Thyroglobulin (Tg) levels dropped in more than half of those who received 131I therapy afterward. Success in redifferentiation can be predicted by a low tumor glycolytic rate, as measured by FDG-PET.