Abstract

Simple SummaryDefining the mechanisms underlying the heterogeneous cancer cell response to DNA damage is important for our ability to tailor individualized strategies to improve chemotherapy efficacy. In this study, we focus on a central DNA repair regulator named VCP whose loss-of-function has been shown by prior studies to increase chemotherapy effects. However, since VCP participates in numerous cellular processes, its total expression level cannot differentiate between VCP-dependent vs. -independent tumors with specific regard to chemotherapy-induced DNA repair. Here, by examining cell lines and patient samples of pancreatic ductal adenocarcinoma (PDAC), we made two major observations. First, DNA damage-induced Ser784 phosphorylation is essential for DNA repair by VCP and drives chemo-resistance. Second, pSer784-VCP instead of total VCP protein predicts cellular reliance on VCP function during DNA repair and consequently chemo-sensitizing effects of VCP inhibition. Thus, pSer784-VCP may be a potential predictive biomarker and sensitizing target for cancer chemotherapy treatments. 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.

Highlights

  • Pancreatic cancer remains the most lethal solid malignancy with >95% of the cases being ductal adenocarcinoma (PDAC)

  • Using an isogenic knockdown and rescue approach, we demonstrated that Ser784 phosphorylation of valosin-containing protein (VCP) is essential for chromatin-associated protein degradation, DNA repair, checkpoint signaling, and cellular survival in response to diverse genotoxic chemotherapeutic treatments

  • DNA Damage-Induced pSer784 -VCP Levels Vary among Pancreatic ductal adenocarcinoma (PDAC) Cell Lines

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Summary

Introduction

Pancreatic cancer remains the most lethal solid malignancy with >95% of the cases being ductal adenocarcinoma (PDAC). It is the third leading cause of cancer-related death in the USA with a 5-year survival rate of ~9% [1,2]. Neither immunotherapy nor targeting driver mutations have achieved significant clinical success so far. Combinatorial chemotherapy regimens such as FOLFIRINOX (leucovorin, 5-fluorouracil, oxaliplatin, irinotecan) and G/A (gemcitabine/paclitaxel) are the mainstay options for PDAC patients [3,4]. Understanding them is important for two main reasons It helps identify chemo-sensitive patients, and spare chemo-resistant patients from unnecessary toxicities. It can provide mechanistic insights to guide the development of chemosensitizing strategies for the chemo-resistant cases

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