Can MDM2 Inhibition With Nutlins Indirectly Restore p53 Function?

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Disruptions of the p53 tumor suppressor pathway play a key role in tumorigenesis and tumor progression in solid and hematologic malignancies.
Disruptions of the p53 tumor suppressor pathway play a key role in tumorigenesis and tumor progression in solid and hematologic malignancies.

The p53 tumor suppressor protein regulates molecular pathways crucial for preventing tumorigenesis, tumor growth, and disease progression, including DNA repair, cell cycle, apoptosis, angiogenesis, and cell senescence pathways.1 TP53 mutations are a key culprit across solid and hematologic cancer types, found in half of human cancer cases: deletion or loss-of-function mutations are common in tumor tissue and blasts across different types of malignancies.2-6 These mutations are less common in some cancers, like multiple myeloma, than others, but they are predictive and prognostic biomarkers of treatment resistance and failure when they do occur.6

Unfortunately, p53 has long been considered an “undruggable” target for tumor control.7

Investigational small molecules targeting p53, such as PRIMA-1 and MIRA-1, have been explored as potential strategies for restoring p53 function.1,7 But toxicity concerns have limited development of MIRA-1.1 APR-246, a derivative of PRIMA-1, underwent phase 1 and 2a clinical testing in patients with hematologic and prostate cancers, with limited evidence of possible responses in a pair of patients with TP53-positive malignancies: 1 with acute myeloid leukemia (AML) and 1 with non-Hodgkin lymphoma.1,8

Early phase APR-246 clinical research continues as part of an investigational combination therapy with pegylated doxorubicin and carboplatin among patients with high-grade ovarian cancer. Research is also under way to determine if zinc can be used to restore mutated p53 structure and function.1,5

Targeting MDM2 To Indirectly Restore p53

As p53's molecular pathways in cancer are becoming better understood, indirect strategies for p53 reactivation are emerging and receiving attention from researchers.

The E3 ubiquitin-protein ligase MDM2 regulatory protein inhibits TP53 tumor suppressor gene transcription. MDM2's own transcription is triggered by p53 — making up the MDM2-p53 feedback loop that regulates normal p53 levels in healthy cells.3,9

In cancers harboring wild-type TP53, which is frequently seen in multiple myeloma, AML, and most other leukemias, for example, p53 is dysregulated by MDM2 oncogene overexpression — opening the door to the possibility of indirect p53 restoration using MDM2 antagonists.3,4,9

Both TP53 mutations and amplified MDM2 gene expression–triggered MDM2 protein production are associated with metastasis, treatment resistance, and poor prognosis in several solid and hematologic malignancies.3,4,6

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