Targeting the p53/xCT/GSH axis with PRIMA-1Met and Sulfasalazine as a potential strategy to prevent therapeutic resistance in Chronic Lymphocytic Leukemia

Chronic lymphocytic Leukemia (CLL) is a highly heterogeneous form of leukemia characterised by complex karyotype aberrations and by gene mutations at different genes including TP53. Mutations in this gene represent a significant hallmark of the disease, thus directing therapeutic decisions, as they can significantly impact the success of treatment protocols. PRIMA-1Met/APR-246/Eprenetapopt is the most clinically advanced mutant p53-targeting agent, which has been shown to reactivate wild-type p53 apoptotic functions. Furthermore, PRIMA-1Met can deplete the glutathione (GHS) reservoir, which levels can also be diminished by Sulfasalazine (SAS), an anti-inflammatory drug. This drug inhibits the xC- transporter, which imports cystine for GSH synthesis. In this study, the association of PRIMA-1Met and SAS was investigated as a strategy to impact on CLL cells by targeting both mutant p53 and GSH pathway. A wild-type and a mutated p53 cell line (OSU-CLL and MEC-1, respectively) were treated with PRIMA-1Met and SAS, alone or in combination, and the results obtained indicated that PRIMA-1Met is unable to restore the wild-type functions in the mutant p53 protein. However, the combination of molecules synergistically decreased cell survival and strongly affected the antioxidant capacity in CLL cells, particularly in the p53-mutated cell line. The same studies have also been performed in CLL primary cells carrying wild-type or mutant p53 and confirmed previous results in CLL cell lines. The association of PRIMA-1Met and SAS represents, therefore, a valid strategy to target CLL cells and prevent the selection of resistant clones able to drive the development of a more aggressive disease.