TY - JOUR
T1 - Panobinostat enhances olaparib efficacy by modifying expression of homologous recombination repair and immune transcripts in ovarian cancer
AU - Wilson, Andrew J.
AU - Gupta, Vijayalaxmi G.
AU - Liu, Qi
AU - Yull, Fiona
AU - Crispens, Marta A.
AU - Khabele, Dineo
N1 - Funding Information:
This research was funded in part by R01CA243511 (DK), R21CA210210 (DK), and R01CA214043 (FY/DK)
Funding Information:
The Translational Pathology Shared Resource is supported by NCI/NIH Cancer Center Support Grant 2P30 CA068485-14. The Vanderbilt Technologies for Advanced Genomics Core is supported by the CTSA Grant (5UL1 RR024975-03), the Vanderbilt Ingram Cancer Center (P30 CA68485), the Vanderbilt Vision Center (P30 EY08126), and NIH/NCRR (G20 RR030956). Members of the Vanderbilt Ovarian Cancer Alliance (VOCAL) are gratefully acknowledged for their support of this work. This research was funded in part by R01CA243511 (DK), R21CA210210 (DK), and R01CA214043 (FY/DK), Not applicable. RNA-seq data files will be made publicly available at the GenBank repository (BioProject Accession PRJNA767427).
Funding Information:
Andrew J. Wilson, Vijayalaxmi G Gupta, Fiona Yull and Qi Liu declare that they do not have any competing interests. Marta A. Crispens reports grants from Astra-Zeneca during the conduct of the study. Dineo Khabele reports grant from NIH R01, Astra Zeneca, during the conduct of the study; receives personal fees from Astra Zeneca and received grants from Deciphera Pharmaceuticals, outside the submitted work.
Funding Information:
The Translational Pathology Shared Resource is supported by NCI/NIH Cancer Center Support Grant 2P30 CA068485-14. The Vanderbilt Technologies for Advanced Genomics Core is supported by the CTSA Grant (5UL1 RR024975-03), the Vanderbilt Ingram Cancer Center (P30 CA68485), the Vanderbilt Vision Center (P30 EY08126), and NIH/NCRR (G20 RR030956). Members of the Vanderbilt Ovarian Cancer Alliance (VOCAL) are gratefully acknowledged for their support of this work.
Publisher Copyright:
© 2021
PY - 2022/2
Y1 - 2022/2
N2 - Histone deacetylase inhibitors (HDACi) sensitize homologous recombination (HR)-proficient human ovarian cancer cells to PARP inhibitors (PARPi). To investigate mechanisms of anti-tumor effects of combined HDACi/PARPi treatment we performed transcriptome analysis in HR- proficient human ovarian cancer cells and tested drug effects in established immunocompetent mouse ovarian cancer models. Human SKOV-3 cells were treated with vehicle (Con), olaparib (Ola), panobinostat (Pano) or Pano+Ola and RNA-seq analysis performed. DESeq2 identified differentially expressed HR repair and immune transcripts. Luciferised syngeneic mouse ovarian cancer cells (ID8-luc) were treated with the HDACi panobinostat alone or combined with olaparib and effects on cell viability, apoptosis, DNA damage and HR efficiency determined. C57BL/6 mice with intraperitoneally injected ID8-luc cells were treated with panobinostat and/or olaparib followed by assessment of tumor burden, markers of cell proliferation, apoptosis and DNA damage, tumor-infiltrating T cells and macrophages, and other immune cell populations in ascites fluid. There was a significant reduction in expression of 20/37 HR pathway genes by Pano+Ola, with immune and inflammatory-related pathways also significantly enriched by the combination. In ID8 cells, Pano+Ola decreased cell viability, HR repair, and enhanced DNA damage. Pano+Ola also co-operatively reduced tumor burden and proliferation, increased tumor apoptosis and DNA damage, enhanced infiltration of CD8+ T cells into tumors, and decreased expression of M2-like macrophage markers. In conclusion, panobinostat in combination with olaparib targets ovarian tumors through both direct cytotoxic and indirect immune-modulating effects.
AB - Histone deacetylase inhibitors (HDACi) sensitize homologous recombination (HR)-proficient human ovarian cancer cells to PARP inhibitors (PARPi). To investigate mechanisms of anti-tumor effects of combined HDACi/PARPi treatment we performed transcriptome analysis in HR- proficient human ovarian cancer cells and tested drug effects in established immunocompetent mouse ovarian cancer models. Human SKOV-3 cells were treated with vehicle (Con), olaparib (Ola), panobinostat (Pano) or Pano+Ola and RNA-seq analysis performed. DESeq2 identified differentially expressed HR repair and immune transcripts. Luciferised syngeneic mouse ovarian cancer cells (ID8-luc) were treated with the HDACi panobinostat alone or combined with olaparib and effects on cell viability, apoptosis, DNA damage and HR efficiency determined. C57BL/6 mice with intraperitoneally injected ID8-luc cells were treated with panobinostat and/or olaparib followed by assessment of tumor burden, markers of cell proliferation, apoptosis and DNA damage, tumor-infiltrating T cells and macrophages, and other immune cell populations in ascites fluid. There was a significant reduction in expression of 20/37 HR pathway genes by Pano+Ola, with immune and inflammatory-related pathways also significantly enriched by the combination. In ID8 cells, Pano+Ola decreased cell viability, HR repair, and enhanced DNA damage. Pano+Ola also co-operatively reduced tumor burden and proliferation, increased tumor apoptosis and DNA damage, enhanced infiltration of CD8+ T cells into tumors, and decreased expression of M2-like macrophage markers. In conclusion, panobinostat in combination with olaparib targets ovarian tumors through both direct cytotoxic and indirect immune-modulating effects.
KW - Histone deacetylase inhibitors
KW - Homologous recombination repair
KW - Immune response
KW - Ovarian cancer
KW - PARP inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85121289667&partnerID=8YFLogxK
U2 - 10.1016/j.neo.2021.12.002
DO - 10.1016/j.neo.2021.12.002
M3 - Article
C2 - 34933276
AN - SCOPUS:85121289667
VL - 24
SP - 63
EP - 75
JO - Neoplasia
JF - Neoplasia
SN - 1522-8002
IS - 2
ER -