The MDM2 Inhibitor AMG 232 Demonstrates Robust Antitumor Efficacy and Potentiates the Activity of p53-Inducing Cytotoxic Agents

Abstract

Abstractp53 is a critical tumor suppressor and is the most frequently inactivated gene in human cancer. Inhibition of the interaction of p53 with its negative regulator MDM2 represents a promising clinical strategy to treat p53 wild-type tumors. AMG 232 is a potential best-in-class inhibitor of the MDM2-p53 interaction and is currently in clinical trials. We characterized the activity of AMG 232 and its effect on p53 signaling in several preclinical tumor models. AMG 232 binds the MDM2 protein with picomolar affinity and robustly induces p53 activity, leading to cell-cycle arrest and inhibition of tumor cell proliferation. AMG 232 treatment inhibited the in vivo growth of several tumor xenografts and led to complete and durable regression of MDM2-amplified SJSA-1 tumors via growth arrest and induction of apoptosis. Therapeutic combination studies of AMG 232 with chemotherapies that induce DNA damage and p53 activity resulted in significantly superior antitumor efficacy and regression, and markedly increased activation of p53 signaling in tumors. These preclinical data support the further evaluation of AMG 232 in clinical trials as both a monotherapy and in combination with standard-of-care cytotoxics.

Small Molecule Inhibition of MDM2–p53 Interaction Augments Radiation Response in Human Tumors

“…1A). Similar to previous studies, the degree of p53 induction varied among different cell lines, likely reflecting differences in the baseline level of p53 and MDM2 as well as the optimal dose/time response to AMG 232 (9). However, a consistent and profound induction of p21 level was observed in all cell lines tested.…”

“…In order to best capture the interaction between AMG 232 and radiation, doses and schedules of both treatment modalities were selected from previous studies (7,9) for each cell line such that single-agent impact on tumor growth inhibition would be modest, in the range of 10% to 30%. Remarkably, in every xenograft model, the combination of AMG 232 and radiation led to superior antitumor efficacy compared with single modality treatment as shown in Fig.…”

“…S1A). AMG 232 robustly activates p53 signaling and has potent antitumor activity in both in vitro and in vivo models (7,9). Emerging evidence has linked MDM2 to the radiation-induced DNA damage repair response by a direct binding to Nbs1 that is a critical member of the Mre11-Nbs1-Rad50 repair pathway (10).…”

The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor Cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 Cascade in the p53^{wild type} Neuroendocrine Tumor Cell Line GOT1

“…Expression of p53 wild type in cancers is essential for their sensitivity to MDM2 inhibitors, as has been demonstrated in many different cancer cell lines in vitro [35,74] . Accordingly, also our own data on p53…”

“…Another preclinical study reported synergistic antitumoral effects of the MDM2 inhibitor AMG 232 together with the cytotoxic compounds cisplatin, carboplatin, doxorubicin, or irinotecan [74] . Co-incubation of AMG 232 with these DNA-damaging, cytotoxic agents caused a synergistic increase in p21 expression [74] .…”