The p53 Reactivating Drug PRIMA-1Met Induces Apoptosis Of Myeloma Cells Via ROS Production

Patients with multiple myeloma (MM) carrying a del(17)(p13) (del17p) deletion and/or TP53 mutation at diagnosis have a shortened survival whatever the treatment received. By using a large and characterized collection of human myeloma cell lines (HMCLs), we have shown that TP53 mutated/deleted cell lines are more resistant to melphalan and nutlin3a (MDM2 inhibitor) than TP53 wild-type HMCLs (Surget S, Cancer Res 2012;72:4562). The absence of a functional p53 pathway prevents the induction of p53 target genes, including pro-apoptotic genes, and therefore impairs apoptosis. In cancer cells, p53 mutations are frequent and highly expressed mutant p53 proteins exert a dominant effect. Pharmacological drugs such as PRIMA-1Met/APR246, which has been recently evaluated in a phase I/II study (Lehmann S J Clin Oncol 2012;30:3633) offers an interesting opportunity to redirect the activity of mutant misfolded p53 proteins. With this aim, the efficiency of PRIMA-1Met was assessed in 22 HMCLs and 16 primary MM samples characterized for del17p. HMCLs were heterogeneously sensitive to PRIMA-1Met, with an LD 50 median value of 35 µM (range 4->100 µM). We failed to observe any correlation with HMCL’s TP53 status since the LD 50 median values of TP53 wt , TP53 mut and TP53 del HMCLs were not significantly different (p=0.1, Kruskal Wallis test) at respectively 21 µM (range 4-70, n=7), 45 µM (21->100, n=13) and 21 µM (8-33, n=2). Primary MM samples were also heterogeneously sensitive, with a median cell death value induced by 10 µM PRIMA-1Met of 51% (n=16, range 5-100%). The 5 del17p+ samples showed no significant difference in their sensitivity to PRIMA-1Met from the 11 del17p- (p=0.31 Mann Whitney). Moreover, the sensitivity of 2 TP53 wt and 2 TP53 mut HMCLs was unchanged upon p53 silencing, and PRIMA-1Met failed to increase the expression of such p53 target genes as p21, Puma or DR5 (TRAIL-R2) in both TP53 wt and TP53 mut/del HMCLs. By contrast, nutlin3a induced cell death and increased DR5 expression in all TP53 wt but in none of the TP53 mut/del HMCLs (p Disclosures: No relevant conflicts of interest to declare.