Reference Detail

Ref Type

Journal Article

PMID

(25567130)

Authors

Canon J, Osgood T, Olson SH, Saiki AY, Robertson R, Yu D, Eksterowicz J, Ye Q, Jin L, Chen A, Zhou J, Cordover D, Kaufman S, Kendall R, Oliner JD, Coxon A, Radinsky R

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	14	3	2015 Mar	649-58	Mol Cancer Ther

URL

Abstract Text

p53 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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 wild-type	lung non-small cell carcinoma	sensitive	KRT-232	Preclinical - Cell line xenograft	Actionable	In a preclinical study, KRT-232 (AMG 232) induced activation of Tp53 target genes and inhibited growth of a non-small cell lung cancer (NSCLC) cell line with wild-type TP53 in culture and inhibited tumor growth in a TP53 wild-type NSCLC cell line xenograft model (PMID: 25567130).	25567130
TP53 wild-type	lung non-small cell carcinoma	sensitive	Carboplatin + KRT-232	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of KRT-232 (AMG 232) and Paraplatin (carboplatin) worked synergistically to inhibit tumor growth in a TP53 wild-type non-small cell lung cancer cell line xenograft model, with increased efficacy over either agent alone (PMID: 25567130).	25567130
TP53 wild-type	lung non-small cell carcinoma	sensitive	Cisplatin + KRT-232	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of KRT-232 (AMG 232) and Platinol (cisplatin) worked synergistically to inhibit tumor growth in a TP53 wild-type non-small cell lung cancer cell line xenograft model, with increased efficacy over either agent alone, resulting in tumor stasis (PMID: 25567130).	25567130
TP53 wild-type	Advanced Solid Tumor	sensitive	KRT-232	Preclinical - Cell line xenograft	Actionable	In a preclinical study, KRT-232 (AMG 232) induced activation of Tp53 target genes and inhibited growth of several human tumor cell lines with wild-type TP53 in culture and in cell line xenograft models (PMID: 25567130).	25567130
TP53 mutant	Advanced Solid Tumor	resistant	KRT-232	Preclinical - Cell culture	Actionable	In a preclinical study, KRT-232 (AMG 232) did not inhibit growth of human tumor cell lines harboring TP53 mutations in culture (PMID: 25567130).	25567130
BRAF mut TP53 wild-type	melanoma	sensitive	KRT-232	Preclinical - Cell line xenograft	Actionable	In a preclinical study, KRT-232 (AMG 232) inhibited growth of a melanoma cell line with wild-type TP53, that also harbored a BRAF mutation, in culture and inhibited tumor growth in a TP53 wild-type BRAF-mutant melanoma cell line xenograft model (PMID: 25567130).	25567130