Targeting p53 in chronic lymphocytic leukemia

Abstract

Introduction: Genomic studies have allowed to identify molecular predictors for chronic lymphocytic leukemia (CLL) treatment tailoring. TP53 disruption is the strongest predictor of chemo-refractoriness and its assessment is the first decisional node in the disease treatment algorithm.

Areas covered: The review covers the p53 biological pathway, its genetic alterations and clinical implications in CLL, and its druggable targets. The potential therapeutic options for TP53 disrupted patients are described, including: i) agents circumventing TP53 disruption; ii) targeted therapies restoring the physiological function of mutant p53; and iii) medicines potentiating p53 function.

Expert opinion: The key approach to improve CLL outcome is treatment tailoring in individual patients. BCR and BCL2 inhibitors have significantly improved CLL survival, however TP53 disrupted patients still have a less favorable outcome than wild type cases, possibly because these novel drugs do not directly target p53 and do not restore the function of the disrupted p53 pathway. Emerging innovative molecules in cancer are able to restore the p53 mutant protein and/or potentiate the activity of the p53 wild type protein. If these compounds were confirmed as efficacious also for CLL, they would represent another step forward in the care of high risk CLL patients with TP53 abnormalities.

Keywords: TP53 targeting; BCL2 inhibitors; BCR inhibitors; chronic lymphocytic leukemia; precision medicine.