p14(ARF) modulates the cytolytic effect of ONYX-015 in mesothelioma cells with wild-type p53

ONYX-015 has been reported to kill selectively tumor cells lacking function al p53. Genetic alterations of INK4a/ARF locus, which is a predominant even t in malignant pleural mesothelioma, may result in loss of p141(ARF) and su bsequent disruption of p53 pathway in cancer cells. In the present study, O NYX-015 was able to kill three mesothelioma cell lines (H28, H513, and 211H ) with wild-type p53 but lacking p14(ARF). In contrast, MS-1 mesothelioma c ells, which expressed both p53 and p14(ARF), were resistant to ONYX-015. In troducing p14(ARF) gene into the H28 cell, a mesothelioma cell without p14 ARF expression, significantly increased the resistance of this cell line to the cytolytic effect of ONYX-015. Our results suggest that human mesotheli omas with wild-type p53 yet lacking p14(ARF) are potential candidates for O NYX-015 therapy.