Targeting the p53 Pathway in CLL: State of the Art and Future Perspectives

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.

ATM Pathway Is Essential for HPV–Positive Human Cervical Cancer-Derived Cell Lines Viability and Proliferation

“…This was also true in cells where E6-AP, a factor required for E6-mediated p53 degradation, was silenced by shRNA. The existence of a synthetic lethal relationship between ATM and p53 has been reported before in different systems and has been revised elsewhere [41,42]. Our results further extend these observations and support the existence of synthetic lethality between p53 and CHEK2, and possibly BRCA1 in HPV-transformed cells.…”

Clonal Evolution of High-Risk Chronic Lymphocytic Leukemia: A Contemporary Perspective

“…Evolutionary herding and clonal homogenization could also be achieved by therapeutically inhibiting the genetic or epigenetic mechanisms underpinning subclonal diversification, or by targeting subclones with the highest level of epigenetic plasticity or genomic instability which are most likely to further diversify and evolve. In relation to the latter, synthetically lethal strategies that target cellular dependencies specific to the most genetically unstable CLL subclones are being investigated ( 165 ); e.g. ATR pathway targeting of TP53 -mutant subclones ( 166 ).…”

Dispirooxindole-β-Lactams: Synthesis via Staudinger Ketene-Imine Cycloaddition and Biological Evaluation

“…Although different ways to inhibit tumor cell proliferation are known, the targeting apoptosis is considered to be the most effective since it potentially leads to a complete elimination of malignant tissues [ 7 , 8 ]. Thus, as a result, strategies based on up-regulation of apoptosis-inducing p53 protein (also known as “genome guardian”) through inhibition of its antagonist, cellular protein MDM2, has become a foundation for the design and synthesis of small-molecule agents for targeted therapy [ 9 , 10 , 11 , 12 , 13 , 14 ]. Several examples of different inhibitors belonging to different structure types are known to exhibit impressive antitumor activity [ 15 , 16 , 17 , 18 ].…”