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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 Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 14 9 2015 Sep 1994-2003 Mol Cancer Ther
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.

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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 melanoma sensitive KRT-232 Preclinical - Cell culture Actionable In a preclinical study, KRT-232 (AMG 232) treatment activated Tp53 signaling and resulted in growth inhibition of TP53 wild-type melanoma cells in culture (PMID: 26162687). 26162687
TP53 wild-type lung cancer sensitive KRT-232 Preclinical - Cell culture Actionable In a preclinical study, KRT-232 (AMG 232) treatment activated Tp53 signaling and resulted in growth inhibition of TP53 wild-type lung cancer cell lines in culture (PMID: 26162687). 26162687
TP53 wild-type osteosarcoma sensitive KRT-232 Preclinical - Cell culture Actionable In a preclinical study, KRT-232 (AMG 232) treatment activated Tp53 signaling and resulted in growth inhibition of TP53 wild-type osteosarcoma cells in culture (PMID: 26162687). 26162687
TP53 wild-type melanoma sensitive KRT-232 + Radiotherapy Preclinical - Cell line xenograft Actionable In a preclinical study, KRT-232 (AMG 232) enhanced radiation-induced cytotoxicity in TP53 wild-type melanoma cells in culture and in cell line xenograft models (PMID: 26162687). 26162687
TP53 wild-type colon cancer sensitive KRT-232 Preclinical - Cell culture Actionable In a preclinical study, KRT-232 (AMG 232) treatment activated Tp53 signaling and resulted in growth inhibition of TP53 wild-type colon cancer cells in culture (PMID: 26162687). 26162687
TP53 wild-type osteosarcoma sensitive KRT-232 + Radiotherapy Preclinical - Cell line xenograft Actionable In a preclinical study, KRT-232 (AMG 232) enhanced radiation-induced cytotoxicity in TP53 wild-type osteosarcoma cells in culture and in cell line xenograft models (PMID: 26162687). 26162687
TP53 wild-type breast cancer sensitive KRT-232 Preclinical - Cell culture Actionable In a preclinical study, KRT-232 (AMG 232) activated Tp53 signaling, resulting in growth inhibition of TP53 wild-type breast cancer cells in culture (PMID: 26162687). 26162687
TP53 wild-type lung cancer sensitive KRT-232 + Radiotherapy Preclinical - Cell line xenograft Actionable In a preclinical study, KRT-232 (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 wild-type colon cancer sensitive KRT-232 + Radiotherapy Preclinical - Cell line xenograft Actionable In a preclinical study, KRT-232 (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 loss lung cancer resistant KRT-232 Preclinical - Cell culture Actionable In a preclinical study, TP53-null lung cancer cells were resistant to KRT-232 (AMG 232) induced growth inhibition in culture (PMID: 26162687). 26162687
TP53 wild-type breast cancer sensitive KRT-232 + Radiotherapy Preclinical - Cell line xenograft Actionable In a preclinical study, KRT-232 (AMG 232) enhanced radiation-induced cytotoxicity in TP53 wild-type breast cancer cells in culture (PMID: 26162687). 26162687
TP53 loss lung cancer resistant KRT-232 + Radiotherapy Preclinical - Cell line xenograft Actionable In a preclinical study, KRT-232 (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