Loss of p14(ARF) in tumor cells facilitates replication of the adenovirus mutant dl1520 (ONYX-015)

The adenovirus mutant dl1520 (ONYX-015) does not express the E1B-55K protei n that binds and inactivates p53. This virus replicates in tumor cells with mutant p53, but not in normal cells with functional p53. Although intra-tu moral 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 p14(ARF ) as a mechanism that allows dl1520 replication in tumor cells retaining wi ld-type p53. We demonstrate that the re-introduction of p14(ARF) into tumor cells with wild-type p53 suppresses replication of dl1520 in a p53-depende nt manner. Our study supports the therapeutic use of dl1520 in tumors with lesions within the p53 pathway other than mutation of p53.