Targeting RPRD1B overcomes chemoresistance in gastric cancer by suppressing the TOPBP1-mediated DNA damage repair pathway.

Authors

Jian Sheng, Jianghua Li, Chenxi Cao, Xiaorong Liu, Chunhua He, Mingjian Fei, Bin Wu, Xiangli Li, Chundong Hu, Shumin Liu, Yahui Lv

Published in

Cellular oncology (Dordrecht, Netherlands). Volume 49. Issue 3. Aug 02, 2026. Epub Aug 02, 2026.

Abstract

Despite the widespread adoption of 5-fluorouracil (5-FU)-based regimens as first-line therapy for gastric cancer, a substantial number of patients develop innate or acquired resistance, highlighting the critical need to identify its underlying molecular drivers. RPRD1B (CREPT), a gene frequently overexpressed in GC, has been clinically associated with advanced tumor stage and poor prognosis. Functionally, RPRD1B promotes aggressive tumorigenic phenotypes by accelerating cell-cycle progression, potentiating proliferative signaling, and enhancing the migratory and invasive capacities of cancer cells. However, its functional role in mediating chemotherapy resistance has not been elucidated.
We established 5-FU-resistant gastric cancer cell lines (from AGS/MGC803 parents via stepwise drug exposure) to study RPRD1B's mechanism, and developed an AAV-based system to therapeutically target RPRD1B to overcome 5-FU resistance.
In this study, we demonstrated that GC patients with high tumor expression of RPRD1B (CREPT) exhibited a poor response to 5-fluorouracil (5-FU)-based chemotherapy. Furthermore, RPRD1B expression was positively correlated with the expression of TOPBP1, a critical DNA damage response and repair effector. Mechanistically, RPRD1B transcriptionally upregulates TOPBP1 by recruiting RNA polymerase II to its promoter, thereby enhancing DNA damage repair. Using an AAV-delivered shRNA to knockdown RPRD1B in a nude mouse xenograft model, we effectively overcame 5-FU resistance in gastric tumors in vivo.
Our findings identify RPRD1B as a promising therapeutic target for reversing chemoresistance in gastric cancer.

PMID:
42542502
Bibliographic data and abstract were imported from PubMed on 02 Aug 2026.

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