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Disruption of FDPS/Rac1 axis radiosensitizes pancreatic ductal adenocarcinoma by attenuating DNA damage response and immunosuppressive signalling.
- Source :
-
EBioMedicine [EBioMedicine] 2022 Jan; Vol. 75, pp. 103772. Date of Electronic Publication: 2021 Dec 28. - Publication Year :
- 2022
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Abstract
- Background: Radiation therapy (RT) has a suboptimal effect in patients with pancreatic ductal adenocarcinoma (PDAC) due to intrinsic and acquired radioresistance (RR). Comprehensive bioinformatics and microarray analysis revealed that cholesterol biosynthesis (CBS) is involved in the RR of PDAC. We now tested the inhibition of the CBS pathway enzyme, farnesyl diphosphate synthase (FDPS), by zoledronic acid (Zol) to enhance radiation and activate immune cells.<br />Methods: We investigated the role of FDPS in PDAC RR using the following methods: in vitro cell-based assay, immunohistochemistry, immunofluorescence, immunoblot, cell-based cholesterol assay, RNA sequencing, tumouroids (KPC-murine and PDAC patient-derived), orthotopic models, and PDAC patient's clinical study.<br />Findings: FDPS overexpression in PDAC tissues and cells (P < 0.01 and P < 0.05) is associated with poor RT response and survival (P = 0.024). CRISPR/Cas9 and pharmacological inhibition (Zol) of FDPS in human and mouse syngeneic PDAC cells in conjunction with RT conferred higher PDAC radiosensitivity in vitro (P < 0.05, P < 0.01, and P < 0.001) and in vivo (P < 0.05). Interestingly, murine (P = 0.01) and human (P = 0.0159) tumouroids treated with Zol+RT showed a significant growth reduction. Mechanistically, RNA-Seq analysis of the PDAC xenografts and patients-PBMCs revealed that Zol exerts radiosensitization by affecting Rac1 and Rho prenylation, thereby modulating DNA damage and radiation response signalling along with improved systemic immune cells activation. An ongoing phase I/II trial (NCT03073785) showed improved failure-free survival (FFS), enhanced immune cell activation, and decreased microenvironment-related genes upon Zol+RT treatment.<br />Interpretation: Our findings suggest that FDPS is a novel radiosensitization target for PDAC therapy. This study also provides a rationale to utilize Zol as a potential radiosensitizer and as an immunomodulator in PDAC and other cancers.<br />Funding: National Institutes of Health (P50, P01, and R01).<br />Competing Interests: Declaration of interests Dr. Surinder K. Batra is one of the co-founders of Sanguine Diagnostics and Therapeutics, Inc. All other authors disclosed no potential conflicts of interest.<br /> (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Cell Line, Tumor
Cell Proliferation
DNA Damage
Gene Expression Regulation, Neoplastic
Geranyltranstransferase genetics
Geranyltranstransferase metabolism
Humans
Mice
Signal Transduction
Tumor Microenvironment genetics
rac1 GTP-Binding Protein genetics
rac1 GTP-Binding Protein metabolism
Carcinoma, Pancreatic Ductal drug therapy
Carcinoma, Pancreatic Ductal genetics
Carcinoma, Pancreatic Ductal radiotherapy
Pancreatic Neoplasms genetics
Pancreatic Neoplasms metabolism
Pancreatic Neoplasms radiotherapy
Subjects
Details
- Language :
- English
- ISSN :
- 2352-3964
- Volume :
- 75
- Database :
- MEDLINE
- Journal :
- EBioMedicine
- Publication Type :
- Academic Journal
- Accession number :
- 34971971
- Full Text :
- https://doi.org/10.1016/j.ebiom.2021.103772