Altogether, this work uncovers RAB3B/DUSP12 as the novel regulators of S6 phosphorylation (S235/236), and suggests the oncogenic and predictive roles of RAB3B/p‐S6 in chordoma, indicating therapeutic potentials of mTORC1‐targeted therapy for advanced chordoma patients with aberrant RAB3B/p‐S6 hyperactivation. Here, RAB3B is linked to chordoma.