Reference Detail

Ref Type Journal Article
PMID (26162687)
Authors Werner LR, Huang S, Francis DM, Armstrong EA, Ma F, Li C, Iyer G, Canon J, Harari PM
Title Small Molecule Inhibition of MDM2-p53 Interaction Augments Radiation Response in Human Tumors.
Journal Molecular cancer therapeutics
Vol 14
Issue 9
Date 2015 Sep
URL
Abstract Text MDM2-p53 interaction and downstream signaling affect cellular response to DNA damage. AMG 232 is a potent small molecule inhibitor that blocks the interaction of MDM2 and p53. We examined the capacity of AMG 232 to augment radiation response across a spectrum of human tumor cell lines and xenografts. AMG 232 effectively inhibited proliferation and enhanced radiosensitivity via inhibition of damage repair signaling. Combined AMG 232 and radiation treatment resulted in the accumulation of γH2AX-related DNA damage and induction of senescence with promotion of apoptotic and/or autophagic cell death. Several molecules involved in senescence, autophagy, and apoptosis were specifically modulated following the combined AMG 232/radiation treatment, including FoxM1, ULK-1, DRAM, and BAX. In vivo xenograft studies confirmed more potent antitumor and antiangiogenesis efficacy with combined AMG 232/radiation treatment than treatment with drug or radiation alone. Taken together, these data identify the capacity of AMG 232 to augment radiation response across a variety of tumor types harboring functional p53.

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 lung cancer sensitive AMG 232 Preclinical - Cell culture Actionable In a preclinical study, AMG 232 activated Tp53 signaling, resulted in growth inhibition of TP53 wild-type lung cancer cell lines in culture (PMID: 26162687). 26162687
TP53 wild-type colon cancer sensitive AMG 232 Preclinical - Cell culture Actionable In a preclinical study, AMG 232 activated Tp53 signaling, resulted in growth inhibition of TP53 wild-type colon cancer cells in culture (PMID: 26162687). 26162687
TP53 wild-type melanoma sensitive AMG 232 Preclinical - Cell culture Actionable In a preclinical study, AMG 232 activated Tp53 signaling, resulted in growth inhibition of TP53 wild-type melanoma cells in culture (PMID: 26162687). 26162687
TP53 wild-type lung cancer sensitive AMG 232 + Radiotherapy Preclinical - Cell line xenograft Actionable In a preclinical study, AMG 232 enhanced radiation-induced cytotoxicity in TP53 wild-type lung cancer cell lines in culture and in cell line xenograft models (PMID: 26162687). 26162687
TP53 loss lung cancer resistant AMG 232 + Radiotherapy Preclinical - Cell line xenograft Actionable In a preclinical study, AMG 232 did not enhance radiation-induced cytotoxicity in TP53-null lung cancer cells in culture and in cell line xenograft models (PMID: 26162687). 26162687
TP53 wild-type osteosarcoma sensitive AMG 232 Preclinical - Cell culture Actionable In a preclinical study, AMG 232 activated Tp53 signaling, resulted in growth inhibition of TP53 wild-type osteosarcoma cells in culture (PMID: 26162687). 26162687
TP53 wild-type breast cancer sensitive AMG 232 + Radiotherapy Preclinical - Cell line xenograft Actionable In a preclinical study, AMG 232 enhanced radiation-induced cytotoxicity in TP53 wild-type breast cancer cells in culture (PMID: 26162687). 26162687
TP53 wild-type melanoma sensitive AMG 232 + Radiotherapy Preclinical - Cell line xenograft Actionable In a preclinical study, AMG 232 enhanced radiation-induced cytotoxicity in TP53 wild-type melanoma cells in culture and in cell line xenograft models (PMID: 26162687). 26162687
TP53 loss lung cancer resistant AMG 232 Preclinical - Cell culture Actionable In a preclinical study, TP53-null lung cancer cells were resistant to AMG 232 induced growth inhibition in culture (PMID: 26162687). 26162687
TP53 wild-type breast cancer sensitive AMG 232 Preclinical - Cell culture Actionable In a preclinical study, AMG 232 activated Tp53 signaling, resulted in growth inhibition of TP53 wild-type breast cancer cells in culture (PMID: 26162687). 26162687
TP53 wild-type colon cancer sensitive AMG 232 + Radiotherapy Preclinical - Cell line xenograft Actionable In a preclinical study, AMG 232 enhanced radiation-induced cytotoxicity in TP53 wild-type colon cancer cells in culture and in cell line xenograft models (PMID: 26162687). 26162687
TP53 wild-type osteosarcoma sensitive AMG 232 + Radiotherapy Preclinical - Cell line xenograft Actionable In a preclinical study, AMG 232 enhanced radiation-induced cytotoxicity in TP53 wild-type osteosarcoma cells in culture and in cell line xenograft models (PMID: 26162687). 26162687