Phospho-ser784-vcp drives resistance of pancreatic ductal adenocarcinoma to genotoxic chemotherapies and predicts the chemo-sensitizing effect of vcp inhibitor

Faliang Wang, Kiran Vij, Lin Li, Paarth Dodhiawala, Kian Huat Lim, Jieya Shao

Research output: Contribution to journalArticlepeer-review

Abstract

Pancreatic ductal adenocarcinoma (PDAC) patients have a dismal prognosis due in large part to chemotherapy resistance. However, a small subset containing defects in the DNA damage response (DDR) pathways are chemotherapy-sensitive. Identifying intrinsic and therapeutically inducible DDR defects can improve precision and efficacy of chemotherapies for PDAC. DNA repair requires dynamic reorganization of chromatin-associated proteins, which is orchestrated by the AAA+ ATPase VCP. We recently discovered that the DDR function of VCP is selectively activated by Ser784 phosphorylation. In this paper, we show that pSer784-VCP but not total VCP levels in primary PDAC tumors negatively correlate with patient survival. In PDAC cell lines, different pSer784-VCP levels are induced by genotoxic chemotherapy agents and positively correlate with genome stability and cell survival. Causal effects of pSer784-VCP on DNA repair and cell survival were confirmed using VCP knockdown and functional rescue. Importantly, DNA damage-induced pSer784-VCP rather than total VCP levels in PDAC cell lines predict their chemotherapy response and chemo-sensitizing ability of selective VCP inhibitor NMS-873. Therefore, pSer784-VCP drives genotoxic chemotherapy resistance of PDAC, and can potentially be used as a predictive biomarker as well as a sensitizing target to enhance the chemotherapy response of PDAC.

Original languageEnglish
Article number5076
JournalCancers
Volume13
Issue number20
DOIs
StatePublished - Oct 1 2021

Keywords

  • Chemotherapy predictive biomarker
  • Chemotherapy resistance
  • DNA damage response
  • Pancreatic ductal adenocarcinoma
  • Synthetic lethality

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