RAB3B Dictates mTORC1/S6 Signaling in Chordoma and Predicts Response to mTORC1-Targeted Therapy

Chordoma, a rare mesenchymal malignancy, exhibits a high tendency to postoperative recurrence and poor prognosis. To date, its tumorigenic regulatory mechanisms remain elusive, leading to a lack of effective therapeutic targets and drug sensitivity indicators. Here, via transcriptome and proteome analyses, RAB3B is unveiled as a prominent oncogenic regulator in chordoma, with high expression and enhancer-associated transcriptional activity. Notably, RAB3B ablation attenuated the chordoma cell stemness and malignant biological properties in vivo and in vitro. Through determining the RAB3B-mediated program in chordoma, it is identified that it enhanced the phosphorylation of S6 specifically at S235/236 and directly bound to S6. Mechanistically, RAB3B physically interacted with phosphorylase DUSP12, and blocked the DUSP12-mediated dephosphorylation of p-S6 (S235/236). Pharmacological targeting mTORC1 pathway dramatically impeded the RAB3B-induced stemness regulation, protein translation, and chordoma tumorigenicity, while RAB3B knockdown desensitized mTORC1 inhibition. In clinic, the combination of RAB3B and p-S6 suggested a good prognostic value and predicted mTORC1 inhibitors response for chordoma patients. 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.