RET inhibition induces apoptosis and markers of cell-cycle arrest, and prominent MAPK-related transcriptomic deregulation in the RET-rearranged models. A, Cells were treated with the indicated doses of selpercatinib, cabozantinib, or vandetanib for 48 hours and then caspase-3/7 activity was determined. Each condition was assayed in triplicate determinations in two independent experiments. Results represent the mean ± SD of one representative experiment. B, Cells were treated with 100 nmol/L selpercatinib for the indicated times and then whole-cell extracts prepared for Western blotting analysis. One representative immunoblot from two independent experiments is shown for each protein. C, Transcriptomic analysis of the overlapping oncogenic and Hallmark signatures that were upregulated in HMSC-RET and SR-Sarc-0001 cells as compared with the parental HMSCs and downregulated in HMSC-RET and SR-Sarc-0001 upon treatment with selpercatinib (6 hours, 100 nmol/L) shows a prominent role for the MAPK pathway.