Important New Insights into Key Regulatory Pathway for Cancer Cell Survival

23
Jun

Gene2

New research from the laboratory of Christine Eischen, PhD, Co-Leader of the Molecular Biology and Genetics Program at the Sidney Kimmel Cancer Center at Jefferson, has revealed a previously unappreciated feature of a well-known cell survival mechanism with potentially important implications for the treatment of some cancers.

The study, recently published in Cancer Research, focuses on the roles of the intensively studied tumor suppressor p53 and its negative regulator Mdm2. In many normal developmental contexts as well as different cancers, the survival of cells depends on a delicate balance of cell death-promoting p53 activity and the opposing cell survival-promoting activity of its binding partner, Mdm2. As indicated by its “tumor suppressor” classification, loss of p53 can allow cancer cells to escape cell death, contributing to tumor survival and progression, as seen in many different p53-deficient cancers. The central role of p53 loss in tumorigenesis is exemplified by the fact that approximately half of all human cancers involve mutation or deletion of p53. Conversely, Mdm2 acts as an oncogenic factor, binding to and inhibiting p53, thereby reducing p53-mediated cell death and contributing to tumor cell survival.

Over the past two decades, numerous studies have led to the view that the primary function of Mdm2 is to regulate p53 and that Mdm2 is unnecessary for survival of cells lacking p53. For example, genetic studies in mice showed that while loss of Mdm2 causes embryonic lethality, this effect is reversed by simultaneous deletion of p53, leading to the widely accepted model that cells can survive without Mdm2 as long as p53 is also absent. According to this model, there should be little or no benefit in targeting Mdm2 for therapeutic purposes in p53-deficient cancers, since Mdm2 would be predicted to have no essential functions in the absence of its key binding partner p53. However, the new Cancer Research study uncovers a key p53-independent function of Mdm2, which Eischen described as “a paradigm-shifting, unexpected discovery that cancer cells lacking p53 need Mdm2 to live.”

The new findings from the Eischen laboratory challenge this dogmatic view of the p53-Mdm2 mechanism by revealing that Mdm2 can regulate cell death in p53-deficient cancer cells by binding to another target, the p73 protein, which is structurally and functionally related to p53. Unlike p53, however, p73 is rarely mutated in human cancer. The researchers found that in T cell lymphomas and sarcomas that lack p53, deletion of Mdm2 is nevertheless able to induce death of cancer cells and thereby prolong survival of mice with these tumors. Similar effects were seen in p53-deficient fibroblasts, indicating that this p53-independent function is a general property of Mdm2 that extends to normal, pre-malignant cells. Intriguingly, loss of Mdm2 resulted in upregulation of p73, suggesting that in some cancer cells, loss of p53 is compensated for by p73, and survival of these cells still requires Mdm2 expression due to the p73:Mdm2 interaction. Eischen noted that further research on the p53-independent activity of Mdm2 is warranted, stating that “we need to further characterize the consequences of loss of Mdm2 in cancer cells that lack functional p53 and further evaluate the role of p73 in mediating the negative effects when Mdm2 is lost.”

These findings have important clinical implications, because even though p53 is mutated or deleted in many cancers, their continued expression of normal p73 provides another route to exploit their dependence on Mdm2 for cancer cell survival. In this scenario for p53-deficient tumors, where compounds targeting p53 or the p53:Mdm2 interaction would be anticipated to have no effect, it might instead be therapeutically effective to target the p73:Mdm2 interaction or Mdm2 itself. As Eischen explained, “our results open a new avenue for therapeutic intervention of the 50% of malignancies lacking functional p53. Our data indicate that targeting Mdm2 in human cancers should have therapeutic benefit regardless of their p53 status.”

For additional information see: Feeley K, Adams CM, Mitra R, and Eischen CM. 2017. p53. Cancer Research. DOI: 10.1158/0008-5472.XN-17-0809. Published January 2017.