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

## TL;DR

RAB3B promotes chordoma cancer growth by affecting mTORC1/S6 signaling and could help predict treatment response to mTORC1 inhibitors.

## Contribution

RAB3B is identified as a novel oncogenic regulator and predictor of mTORC1 inhibitor response in chordoma.

## Key findings

- RAB3B enhances S6 phosphorylation by blocking DUSP12-mediated dephosphorylation.
- RAB3B ablation reduces chordoma cell stemness and malignancy in vitro and in vivo.
- RAB3B/p-S6 combination predicts mTORC1 inhibitor response and has prognostic value in chordoma patients.

## Abstract

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.

RAB3B is unveiled as a prominent oncogenic regulator in chordoma, which can block the DUSP12‐mediated dephosphorylation of p‐S6 (S235/236). The combination of RAB3B and p‐S6 indicates a good prognostic value and predicts mTORC1 inhibitors response for chordoma patients. This approach enables therapeutic potentials of mTORC1‐targeted therapy for advanced chordoma patients with aberrant RAB3B/p‐S6 hyperactivation.