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	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	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 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	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 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	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 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	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	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	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 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