PRIMA-1(met) (APR-246) inhibits growth of colorectal cancer cells with different p53 status through distinct mechanisms

PRIMA-1(met) (APR-246) is a methylated derivative and structural analog of PRIMA-1 (p53 re-activation and induction of massive apoptosis). PRIMA-1(met) has been reported to restore both the wild type (wt) structure and function of mutant p53. Here, we show that PRIMA-1(met) is highly effective at limiting the growth of CRC cells regardless of p53 status. However, PRIMA-1(met) induces robust apoptosis only in CRC cells with mutant p53. Upregulation of Noxa, a proapoptotic molecule, is crucial for PRIMA-1(met) mediated activity. In human xenograft model of disease, PRIMA-1(met) effectively suppresses CRC tumor growth. Our results uncover distinct mechanisms of PRIMA-1(met) in CRC with different p53 status, thus providing a mechanistic rationale to evaluate the clinical efficacy of PRIMA-1(met) in CRC patients with different p53 status.