p21 Promotes oncolytic adenoviral activity in ovarian cancer and is a potential biomarker.
The oncolytic adenovirus dl922-947 replicates selectively within and lyses cells with a dysregulated Rb pathway, a finding seen in > 90% human cancers. dl922-947 is more potent than wild type adenovirus and the E1B-deletion mutant dl1520 (Onyx-015). We wished to determine which host cell factors influence cytotoxicity. SV40 large T-transformed MRC5-VA cells are 3-logs more sensitive to dl922-947 than isogenic parental MRC5 cells, confirming that an abnormal G1/S checkpoint increases viral efficacy. The sensitivity of ovarian cancer cells to dl922-947 varied widely: IC50 values ranged from 51 (SKOV3ip1) to 0.03 pfu/cell (TOV21G). Cells sensitive to dl922-947 had higher S phase populations and supported earlier E1A expression. Cytotoxicity correlated poorly with both infectivity and replication, but well with expression of p21 by microarray and western blot analyses. Matched p21+/+ and -/- Hct116 cells confirmed that p21 influences dl922-947 activity in vitro and in vivo. siRNA-mediated p21 knockdown in sensitive TOV21G cells decreases E1A expression and viral cytotoxicity, whilst expression of p21 in resistant A2780CP cells increases virus activity in vitro and in intraperitoneal xenografts. These results highlight that host cell factors beyond simple infectivity can influence the efficacy of oncolytic adenoviruses. p21 expression may be an important biomarker of response in clinical trials.
Flak
Magdalena B
MB
Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and the London School of Medicine, Queen Mary University of London, London EC1 M 6BQ, UK.
Connell
Claire M
CM
Chelala
Claude
C
Archibald
Kyra
K
Salako
Michael A
MA
Pirlo
Katrina J
KJ
Lockley
Michelle
M
Wheatley
Sally P
SP
Balkwill
Frances R
FR
McNeish
Iain A
IA
D000256:Adenoviridae / Q000502:physiology*; D017500:Adenovirus E1A Proteins / Q000378:metabolism; D056741:Cyclin D / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000502:physiology*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D006863:Hydrogen-Ion Concentration; D050130:Oncolytic Virotherapy; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy / Q000821:virology*; D016196:S Phase
D017500:Adenovirus E1A Proteins; C493956:CDKN1A protein, human; D056741:Cyclin D; D050759:Cyclin-Dependent Kinase Inhibitor p21