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 functional p53. Genetic alterations of INK4a/ARF locus, which is a predominant event in malignant pleural mesothelioma, may result in loss of p14^ARF and subsequent disruption of p53 pathway in cancer cells. In the present study, ONYX-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 cells, which expressed both p53 and p14^ARF were resistant to ONYX-015. Introducing 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 mesotheliomas with wild-type p53 yet lacking p14^ARF are potential candidates for ONYX-015 therapy.