CSIG-35. RAB3B DICTATES MTORC1/S6 SIGNALING IN CHORDOMA AND PREDICTS RESPONSE TO MTORC1-TARGETED THERAPY

Abstract Chordoma is a rare mesenchymal malignancy, exhibiting 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, we unveiled RAB3B as the prominent oncogenic regulator in chordoma. Multidimensional tissue samples further indicated its overexpression and enhancer-associated high transcriptional activity in chordoma. Notably, RAB3B ablation attenuated the chordoma cell growth, stemness, migration and tumorigenicity in vivo and in vitro. Through determining the RAB3B-mediated program in chordoma, we identified that RAB3B was highly associated with PI3K-AKT-mTOR signaling and directly bound to S6. Mechanistically, RAB3B increased the S6K-mediated phosphorylation of S6 by physically interacting with dephosphorylase DUSP12, to block its dephosphorylating of p-S6 specifically at S235/236. Pharmacological targeting mTORC1 pathway via dactolisib and rapamycin dramatically impeded the RAB3B-induced chordoma cell oncogenesis, while RAB3B knockout desensitized mTORC1 inhibition. Clinically, RAB3B/p-S6 suggested a good prognostic value and response to mTORC1 inhibitors for chordoma patients. Altogether, this work uncovers RAB3B as a novel activator of mTORC1 pathway, and suggests the oncogenic and predictive roles of RAB3B/p-S6 in chordoma, indicating therapeutic potentials of mTORC1-targeted therapy in advanced chordoma patients with aberrant RAB3B/p-S6 hyperactivation.