Loss of p14ARF in tumor cells facilitates replication of the adenovirus mutant dl1520 (ONYX-015).
The adenovirus mutant dl1520 (ONYX-015) does not express the E1B-55K protein that binds and inactivates p53. This virus replicates in tumor cells with mutant p53, but not in normal cells with functional p53. Although intra-tumoral injection of dl1520 shows promising responses in patients with solid tumors, previous in vitro studies have not established a close correlation between p53 status and dl1520 replication. Here we identify loss of p14ARF as a mechanism that allows dl1520 replication in tumor cells retaining wild-type p53. We demonstrate that the re-introduction of p14ARF into tumor cells with wild-type p53 suppresses replication of dl1520 in a p53-dependent manner. Our study supports the therapeutic use of dl1520 in tumors with lesions within the p53 pathway other than mutation of p53.
Ries
S J
SJ
Cancer Research Institute, Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143-0128, USA.
Brandts
C H
CH
Chung
A S
AS
Biederer
C H
CH
Hann
B C
BC
Lipner
E M
EM
McCormick
F
F
Korn
W M
WM
D000256:Adenoviridae / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D014407:Tumor Cells, Cultured / Q000821:virology; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2