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Loss of p14ARF in tumor cells facilitates replication of the adenovirus mutant dl1520 (ONYX-015)
Authors:Ries S J  Brandts C H  Chung A S  Biederer C H  Hann B C  Lipner E M  McCormick F  Korn W M
Affiliation:Cancer Research Institute, Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143-0128, USA.
Abstract: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.
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