Abstract
Since the discovery of the first MDM2 inhibitors, we have gained deeper insights into the cellular roles of MDM2 and p53. In this review, we focus on MDM2 inhibitors that bind to the p53-binding domain of MDM2 and aim to disrupt the binding of MDM2 to p53. We describe the basic mechanism of action of these MDM2 inhibitors, such as nutlin-3a, summarise the determinants of sensitivity to MDM2 inhibition from p53-dependent and p53-independent points of view and discuss the problems with innate and acquired resistance to MDM2 inhibition. Despite progress in MDM2 inhibitor design and ongoing clinical trials, their broad use in cancer treatment is not fulfilling expectations in heterogenous human cancers. We assess the MDM2 inhibitor types in clinical trials and provide an overview of possible sources of resistance to MDM2 inhibition, underlining the need for patient stratification based on these aspects to gain better clinical responses, including the use of combination therapies for personalised medicine.
Highlights
Since the discovery of the first MDM2 inhibitors, we have gained deeper insights into the cellular roles of MDM2 and p53
The overall outcome of this activation varies greatly due to multiple factors that influence p53 pathway activation or p53-independent MDM2 functions (Fig. 5)
Improved understanding of the specific pathway(s) responsible for resistance in an individual patient will aid the prediction of their specific biomarker—a panel of markers rather than a single marker will need to be assessed for optimal use of MDM2 inhibitors in personalised medicine
Summary
Resistance mechanisms to inhibitors of p53‐MDM2 interactions in cancer therapy: can we overcome them?. Lucia Haronikova1*, Ondrej Bonczek, Pavlina Zatloukalova, Filip Kokas‐Zavadil, Martina Kucerikova, Philip J.
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