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 Molecular cancer therapeutics
Vol 14
Issue 3
Date 2015 Mar
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.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
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 Advanced Solid Tumor sensitive AMG 232 Preclinical - Cell line xenograft Actionable In a preclinical study, 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 wild-type non-small cell lung carcinoma sensitive AMG 232 Preclinical - Cell line xenograft Actionable In a preclinical study, 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
KRAS mut + TP53 wild-type colorectal cancer sensitive AMG 232 + Irinotecan Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of AMG 232 and Camptosaur (irinotecan) inhibited tumor growth in a TP53 wild-type colorectal cancer cell line xenograft model, which also harbors a KRAS mutation, with increased efficacy over either agent alone (PMID: 25567130). 25567130
BRAF mut + TP53 wild-type melanoma sensitive AMG 232 Preclinical - Cell line xenograft Actionable In a preclinical study, 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
TP53 wild-type non-small cell lung carcinoma sensitive AMG 232 + Carboplatin Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of 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
KRAS mut + TP53 wild-type colorectal cancer sensitive AMG 232 Preclinical - Cell line xenograft Actionable In a preclinical study, AMG 232 induced activation of Tp53 target genes and inhibited growth of a colorectal cancer (CRC) cell line with wild-type TP53, that also harbored a KRAS mutation, in culture and inhibited tumor growth in a TP53 wild-type KRAS-mutant CRC cell line xenograft model (PMID: 25567130). 25567130
TP53 mutant Advanced Solid Tumor resistant AMG 232 Preclinical - Cell culture Actionable In a preclinical study, AMG 232 did not inhibit growth of human tumor cell lines harboring TP53 mutations in culture (PMID: 25567130). 25567130
TP53 wild-type non-small cell lung carcinoma sensitive AMG 232 + Cisplatin Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of 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