Telomerase-independence function of Dyskerin is therapeutic vulnerability in p53 mutant pancreatic neuroendocrine tumors

Author:

Ji Shunrong1ORCID,Lou Xin2,Xu Junfeng2,Shi Yihua2,Qin Yi3,Zhang WuhuORCID,Ye Zeng4,Wang Fei2,Wang Yan2,Jing Desheng2,Fan Guixiong2,Zhang Yue5,Chen Xuemin5,Chen Jie2,Xu XiaowuORCID,Yu Xianjun3ORCID

Affiliation:

1. Pancreatic Cancer Institute, Fudan University, Fudan University

2. Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center

3. Fudan University Shanghai Cancer Center

4. Shanghai Pancreatic Cancer Institute

5. The First People’s Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, China

Abstract

Abstract Pancreatic neuroendocrine tumors (PanNETs) use the recombination-mediated alternative lengthening of telomeres (ALT) mechanism, instead of telomerase, for telomere maintenance, while the relationship between this mechanism and clinical practice is still unknown, especially chemotherapy resistance. Here, we found Temozolomide (TMZ) activated the RNA-binding protein dyskerin, encoded by DKC1 gene which functions as a core component of the telomerase holoenzyme. The upregulation of dyskerin dramatically elevated Wnt signaling in p53-mutant PanNETs independent of telomerase, contributing to drug resistance and recurrence after treatment. Mutant p53-driven DKC1 activation enhanced CTNNB1/TCF transcription, leading to Wnt/β-catenin pathway activation in patient-derived tumor cells (PDCs), patient-derived tumor organoids (PDOs) and patient-derived tumor xenografts (PDXs). TMZ-induced Wnt/β-catenin pathway activation could enhance the subsequent DNA damage repair, contributing to drug resistance. Combination treatment with a DKC1 inhibitor and TMZ effectively enhanced DNA damage and reduced tumor regrowth. Together, our findings highlight dyskerin as a new therapeutic target in PanNETs with crucial telomerase-independent functions. Mechanically, mutant p53-mediated dyskerin as a critical mediator of TMZ induced DNA damage repair via the β-catenin/TCF pathway and highlighted combination treatment with a dyskerin inhibitor and TMZ as a compelling therapeutic strategy to improve the poor outcomes of current TMZ-based therapies for PanNETs patients.

Publisher

Research Square Platform LLC

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