•Sensitivity of BRAF-mutated tumors to trametinib is due, in part, to MAPK-mediated regulation of TORC1 activity•Resistance to trametinib is driven by upregulated MAPK pathway and downregulated TORC1 pathway•Resistance to trametinib is tumor line-specific and drug-specific. Here, CRTC1 is linked to neoplasm.