Reference Detail

Ref Type

Journal Article

PMID

(32655895)

Authors

Sahin I, Zhang S, Navaraj A, Zhou L, Dizon D, Safran H, El-Deiry WS

Title

AMG-232 sensitizes high MDM2-expressing tumor cells to T-cell-mediated killing.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cell death discovery	6		2020	57	Cell Death Discov

URL

Abstract Text

Oncogenic mouse double minute 2 homolog (MDM2) is an E3-ubiquitin ligase that facilitates proteasomal degradation of p53. MDM2 amplification occurs in cancer and has been implicated in accelerated tumor growth, known as hyper-progression, following immune-checkpoint therapy. MDM2 amplification also predicts poor response to immune-checkpoint inhibitors. We sought to evaluate the role of MDM2 in T-cell-mediated immune resistance. Ovarian clear cell carcinoma cell lines carrying wild-type p53 with low/high MDM2 expression were investigated in a T-cell co-culture system evaluating T-cell-mediated tumor killing. Targeting of MDM2 was achieved by siRNA transfection or a selective MDM2 inhibitor, AMG-232 and tumor cells were tested in the T-cell co-culture system. AMG-232 activated p53 signaling in cancer cells and relative resistance to AMG-232 was observed in high MDM2-expressing cell lines. Cell lines with high MDM2 expression were more resistant to T cell-mediated tumor killing. Targeting MDM2 by gene-silencing or pharmacological blockade with AMG-232 enhanced T-cell killing of cancer cells. AMG-232 potentiated tumor cell killing by T-cells in combination with anti-PD-1 antibody treatment, regardless of changes in PD-L1 expression. The AMG-232 was not toxic to the T-cells. MDM2 inhibition lowered expression of Interleukin-6, a pro-inflammatory pro-tumorigenic cytokine. Our data support targeting MDM2 in tumors with overexpression or amplification of MDM2 as a precision therapy approach to overcome drug resistance including hyper-progression in the context of immune checkpoint therapy.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. 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 on a longer phrase with spaces (i.e. "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	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
MDM2 over exp TP53 wild-type	ovarian clear cell carcinoma	predicted - sensitive	KRT-232	Preclinical - Cell culture	Actionable	In a preclinical study, KRT-232 (AMG 232) treatment sensitized ovarian clear cell carcinoma cell lines harboring wild-type TP53 and MDM2 overexpression to T-cell mediated killing when co-cultured with T-cells, demonstrating decreased cell viability (PMID: 32655895).	32655895
MDM2 over exp TP53 wild-type	ovarian clear cell carcinoma	predicted - sensitive	KRT-232 + Pembrolizumab	Preclinical - Cell culture	Actionable	In a preclinical study, an ovarian clear cell carcinoma cell line harboring wild-type TP53 and MDM2 overexpression was sensitive to combination treatment with KRT-232 (AMG 232) and Keytruda (pembrolizumab) when co-cultured with T cells, demonstrating increased T-cell mediated cell death (PMID: 32655895).	32655895