The pre-clinical development of MDM2 inhibitors in chronic lymphocytic leukemia uncovers a central role for p53 status in sensitivity to MDM2 inhibitor-mediated apoptosis

Cell Cycle
Dale BixbySami N Malek

Abstract

Inhibitors of the MDM2-p53 interaction are actively being developed as anti-cancer agents. Drug-induced interference with the MDM2 E3 ligase function or with MDM2 protein-protein interactions abrogates tonic suppression and destruction of the p53 protein; consequently, p53 steady state levels rise resulting in the induction of p53-dependent anti-proliferative and pro-apoptotic genes. Some cancerous cells harboring wild type p53 respond to MDM2 inhibitor-induced elevated p53 protein levels with apoptotic cell death while non-malignant cells, for poorly understood reasons, appear relatively resistant. Deciphering the mechanisms of resistance or susceptibility to MDM2 inhibitor-induced cancer cell death is of significant importance for the clinical development and applications of MDM2 inhibitory compounds and serves to illuminate aspects of MDM2 and p53 biology. Using data from ex vivo MDM2 inhibitor treatment of a large cohort of molecularly highly characterized CLL cases, we were able to demonstrate the central role of p53 status as a determinant of resistance in this common leukemia. In the context of these experimental findings, we summarize pertinent knowledge of the biology of p53, MDM2, p53 target genes and MDM2 binding pro...Continue Reading

Citations

Dec 15, 2010·Current Hematologic Malignancy Reports·Xavier C BadouxWilliam G Wierda
Jan 28, 2012·Leukemia & Lymphoma·Emeline de VironEric Van Den Neste
Nov 18, 2008·Expert Opinion on Investigational Drugs·Sharmila Patel, Mark R Player
Apr 27, 2017·British Journal of Haematology·Hussein GhamlouchOlivier A Bernard
Apr 11, 2014·International Journal of Oncology·Atsuko NakanishiSatoru Matsuda
Jul 8, 2016·Anti-cancer Drugs·Yong-Song GuanQing Zou
Dec 17, 2021·Cellular & Molecular Biology Letters·Lucia HaronikovaBorivoj Vojtesek

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