EXTH-05. RAB3B/DUSP12 mediates S6-mediated protein translation and predicts clinical response to mTORC1 inhibitors in chordoma

Chordoma is a relatively rare malignancy mainly located in skull base and sacrum. Due to the aggressive nature, chordoma 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 multi-omics analyses, RAB3B is unveiled as a prominent oncogenic regulator in chordoma, with enhancer-associated transcriptional activity and high expression levels and. Genetical ablation of RAB3B significantly weakens the cell stemness and malignant biological properties of chordoma in vivo and in vitro. To determine 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. To further explore the clinical roles of this regulation, we identified that the combination of RAB3B and p-S6 suggested a good prognostic value. Additionally, they predicted clinical response to mTORC1 inhibitors in chordoma patients. In conclusion, 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.