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Targeting TP53 disruption in chronic lymphocytic leukemia: Current strategies and future directions

Molica, Stefano; Tam, Constantine; Allsup, David; Polliack, Aaron

Authors

Stefano Molica

Constantine Tam

Aaron Polliack



Abstract

In the modern era of Chronic Lymphocytic Leukemia (CLL) targeted therapy, the loss of p53 function due to genetic abnormalities remains a significant challenge. This is because even targeted agents, which are currently the mainstay of treatment for CLL, do not directly target p53 or restore its disrupted pathway. Consequently, resistance to therapy and unfavorable clinical outcomes often accompany these p53-related abnormalities. An essential goal of future clinical research should be to address the ostensibly “undruggable” p53 pathway. Currently, multiple therapeutic approaches are being explored to tackle TP53 dysfunction and improve outcomes in high-risk CLL. These approaches include the use of oncoprotein murine double minute 2 inhibitors, small-molecule p53 reactivators, exportin 1 (XPO1) inhibitors, and ataxia-telangiectasia mutated and Rad3-related (ATR) inhibitors. Combinations of these p53-targeting strategies, along with established novel therapies such as B-cell receptor or B-cell lymphoma-2 (BCL-2) inhibitors, may shape the future of therapeutic trials in this challenging-to-treat disease.

Citation

Molica, S., Tam, C., Allsup, D., & Polliack, A. (in press). Targeting TP53 disruption in chronic lymphocytic leukemia: Current strategies and future directions. Hematological Oncology, https://doi.org/10.1002/hon.3238

Journal Article Type Article
Acceptance Date Oct 19, 2023
Online Publication Date Nov 8, 2023
Deposit Date Nov 8, 2023
Publicly Available Date Nov 9, 2024
Journal Hematological Oncology
Print ISSN 0278-0232
Electronic ISSN 1099-1069
Publisher Wiley
Peer Reviewed Peer Reviewed
DOI https://doi.org/10.1002/hon.3238
Keywords CLL; Current strategies; Novel therapies; Targeting TP53 aberrations
Public URL https://hull-repository.worktribe.com/output/4435366

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Copyright Statement
This is the peer reviewed version of the following article: Molica S, Tam C, Allsup D, Polliack A. Targeting TP53 disruption in chronic lymphocytic leukemia: current strategies and future directions. Hematol Oncol. 2023; 1-9., which has been published in final form at https://doi.org/10.1002/hon.3238. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.





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