TY - JOUR
T1 - Disruption of FDPS/Rac1 axis radiosensitizes pancreatic ductal adenocarcinoma by attenuating DNA damage response and immunosuppressive signalling
AU - Seshacharyulu, Parthasarathy
AU - Halder, Sushanta
AU - Nimmakayala, Ramakrishna
AU - Rachagani, Satyanarayana
AU - Chaudhary, Sanjib
AU - Atri, Pranita
AU - Chirravuri-Venkata, Ramakanth
AU - Ouellette, Michel M.
AU - Carmicheal, Joseph
AU - Gautam, Shailendra K.
AU - Vengoji, Raghupathy
AU - Wang, Shuo
AU - Li, Sicong
AU - Smith, Lynette
AU - Talmon, Geoffrey A.
AU - Klute, Kelsey
AU - Ly, Quan
AU - Reames, Bradley N.
AU - Grem, Jean L.
AU - Berim, Lyudmyla
AU - Padussis, James C.
AU - Kaur, Sukhwinder
AU - Kumar, Sushil
AU - Ponnusamy, Moorthy P.
AU - Jain, Maneesh
AU - Lin, Chi
AU - Batra, Surinder K.
N1 - Publisher Copyright:
© 2021 The Author(s)
PY - 2022/1
Y1 - 2022/1
N2 - 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).
AB - 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).
KW - FDPS
KW - PDAC
KW - Radioresistance
KW - Radiotherapy
KW - Zoledronic acid
UR - http://www.scopus.com/inward/record.url?scp=85121972956&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85121972956&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2021.103772
DO - 10.1016/j.ebiom.2021.103772
M3 - Article
C2 - 34971971
AN - SCOPUS:85121972956
SN - 2352-3964
VL - 75
JO - EBioMedicine
JF - EBioMedicine
M1 - 103772
ER -