ONYX-015 selectivity and the p14ARF pathway

Abstract

ONYX-015, dl1520, is an adenovirus that lacks the E1B 55K gene and therefore lacks the capacity to neutralize p53 during infection. This virus induces high levels of p53 and fails to grow efficiently in primary epithelial cells. However, it does replicate in many tumor cells, including those expressing wild-type p53. In these cells, ONYX-015 fails to induce active p53. This is because the pathway from E1a to p53 is disrupted through loss of p14ARF. We propose that high levels of Mdm2 activity resulting from loss of p14ARF, and high levels of Mdm2 protein resulting from activated Ras prevent accumulation of functional p53 during infection of tumor cells that retain wild-type p53.