LAUSR

Simple Summary The p53 pathway plays a fundamental role in preventing the accumulation of unrepaired DNA damage. Unsurprisingly, cancer cells often break this protective barrier by inactivating either p53 itself or other proteins along this pathway, such as ATM. This facilitates the acquisition of further alterations that are required for unperturbed cancer growth and the development of chemoresistance. Over the years, there has been substantial scientific investment in creating new cancer therapies that can overcome functional loss of the p53 pathway. In this review, we will discuss different therapeutic approaches towards achieving this goal within the context of chronic lymphocytic leukemia (CLL), a cancer type with a p53-deficient subset that remains challenging to treat. Abstract The p53 pathway is a desirable therapeutic target, owing to its critical role in the maintenance of genome integrity. This is exemplified in chronic lymphocytic leukemia (CLL), one of the most common adult hematologic malignancies, in which functional loss of p53 arising from genomic aberrations are frequently associated with clonal evolution, disease progression, and therapeutic resistance, even in the contemporary era of CLL targeted therapy and immunotherapy. Targeting the ‘undruggable’ p53 pathway therefore arguably represents the holy grail of cancer research. In recent years, several strategies have been proposed to exploit p53 pathway defects for cancer treatment. Such strategies include upregulating wild-type p53, restoring tumor suppressive function in mutant p53, inducing synthetic lethality by targeting collateral genome maintenance pathways, and harnessing the immunogenicity of p53 pathway aberrations. In this review, we will examine the biological and clinical implications of p53 pathway defects, as well as our progress towards development of therapeutic approaches targeting the p53 pathway, specifically within the context of CLL. We will appraise the opportunities and pitfalls associated with these therapeutic strategies, and evaluate their place amongst the array of new biological therapies for CLL.