Authors

Parthasarathy Seshacharyulu, University of Nebraska Medical CenterFollow
Sushanta Halder, University of Nebraska Medical CenterFollow
Rama Krishna Nimmakayala, University of Nebraska Medical CenterFollow
Satyanarayana Rachagani, University of Nebraska Medical CenterFollow
Sanjib Chaudhary, University of Nebraska Medical CenterFollow
Pranita Atri, University of Nebraska Medical CenterFollow
Ramakanth C. Venkata, University of Nebraska Medical CenterFollow
Michel M. Ouellette, University of Nebraska Medical CenterFollow
Joseph Carmicheal, University of Nebraska Medical CenterFollow
Shailendra K. Gautam, University of Nebraska Medical CenterFollow
Raghupathy Vengoji, University of Nebraska Medical CenterFollow
Shuo Wang, University of Nebraska Medical CenterFollow
Sicong Li, University of Nebraska Medical CenterFollow
Lynette M. Smith, University of Nebraska-LincolnFollow
Geoffrey A. Talmon, University of Nebraska Medical CenterFollow
Kelsey Klute, University of Nebraska Medical CenterFollow
Quan P. Ly, University of Nebraska Medical CenterFollow
Bradley N. Reames, University of Nebraska Medical CenterFollow
Jean L. Grem, University of Nebraska Medical CenterFollow
Lyudmyla Berim, Rutgers University - New Brunswick/Piscataway
James C. Padussis, University of Nebraska Medical CenterFollow
Sukhwinder Kaur, University of Nebraska Medical CenterFollow
Sushil Kumar, University of Nebraska Medical CenterFollow
Moorthy P. Ponnusamy, University of Nebraska Medical CenterFollow
Maneesh Jain, University of Nebraska Medical CenterFollow
Chi Lin, University of Nebraska Medical CenterFollow
Surinder K. Batra, University of Nebraska Medical CenterFollow

Document Type

Article

Journal Title

EBioMedicine

Publication Date

2021

Volume

75

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.

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.

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.

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.

FUNDING: National Institutes of Health (P50, P01, and R01).

ISSN

2352-3964

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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