Reference Detail

Ref Type

Journal Article

PMID

(36734633)

Authors

Adams CM, Mitra R, Xiao Y, Michener P, Palazzo J, Chao A, Gour J, Cassel J, Salvino JM, Eischen CM

Title

Targeted MDM2 Degradation Reveals a New Vulnerability for p53-Inactivated Triple-Negative Breast Cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	13	5	2023 May 04	1210-1229	Cancer Discov

URL

Abstract Text

Triple-negative breast cancers (TNBC) frequently inactivate p53, increasing their aggressiveness and therapy resistance. We identified an unexpected protein vulnerability in p53-inactivated TNBC and designed a new PROteolysis TArgeting Chimera (PROTAC) to target it. Our PROTAC selectively targets MDM2 for proteasome-mediated degradation with high-affinity binding and VHL recruitment. MDM2 loss in p53 mutant/deleted TNBC cells in two-dimensional/three-dimensional culture and TNBC patient explants, including relapsed tumors, causes apoptosis while sparing normal cells. Our MDM2-PROTAC is stable in vivo, and treatment of TNBC xenograft-bearing mice demonstrates tumor on-target efficacy with no toxicity to normal cells, significantly extending survival. Transcriptomic analyses revealed upregulation of p53 family target genes. Investigations showed activation and a required role for TAp73 to mediate MDM2-PROTAC-induced apoptosis. Our data, challenging the current MDM2/p53 paradigm, show MDM2 is required for p53-inactivated TNBC cell survival, and PROTAC-targeted MDM2 degradation is an innovative potential therapeutic strategy for TNBC and superior to existing MDM2 inhibitors.p53-inactivated TNBC is an aggressive, therapy-resistant, and lethal breast cancer subtype. We designed a new compound targeting an unexpected vulnerability we identified in TNBC. Our MDM2-targeted degrader kills p53-inactivated TNBC cells, highlighting the requirement for MDM2 in TNBC cell survival and as a new therapeutic target for this disease. See related commentary by Peuget and Selivanova, p. 1043. This article is highlighted in the In This Issue feature, p. 1027.

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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
YX-02-030	YX-02-030	8	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
YX-02-030		YX-02030\|YX 02030\|YX 02 030	MDM2 Inhibitor 23	YX-02-030 is a proteolysis-targeted chimera (PROTAC) that binds to MDM2 and targets it for degradation, potentially leading to tumor cell death (PMID: 36734633).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
TP53	D281Y	missense	unknown	TP53 D281Y lies within the DNA-binding domain of the Tp53 protein (PMID: 22713868). D281Y has been identified in the scientific literature (PMID: 36734633), but has not been biochemically characterized and therefore, its effect on Tp53 protein function is unknown (PubMed, Feb 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
MDM2 pos TP53 G266E	triple-receptor negative breast cancer	sensitive	YX-02-030	Preclinical - Patient cell culture	Actionable	In a preclinical study, YX-02-030 decreased Mdm2 expression and increased apoptosis in patient-derived triple-negative breast cancer explants harboring TP53 G266E in culture (PMID: 36734633).	36734633
MDM2 pos TP53 del	triple-receptor negative breast cancer	sensitive	YX-02-030	Preclinical - Cell line xenograft	Actionable	In a preclinical study, YX-02-030 decreased Mdm2 expression, increased apoptosis, and decreased survival, colony formation, and mammosphere formation in triple-negative breast cancer cell lines harboring TP53 deletion in culture, and decreased tumor growth and increased survival in a cell line xenograft model (PMID: 36734633).	36734633
MDM2 pos TP53 R175H	triple-receptor negative breast cancer	sensitive	YX-02-030	Preclinical - Cell culture	Actionable	In a preclinical study, YX-02-030 decreased Mdm2 expression and survival in triple-negative breast cancer cells harboring TP53 R175H in culture (PMID: 36734633).	36734633
MDM2 pos TP53 R248Q	triple-receptor negative breast cancer	sensitive	YX-02-030	Preclinical - Patient cell culture	Actionable	In a preclinical study, YX-02-030 decreased survival in a triple-negative breast cancer (TNBC) cell line harboring TP53 R248Q in culture, decreased Mdm2 expression and increased apoptosis in patient-derived TNBC explants in culture, and increased apoptosis and decreased survival in 3D mammosphere cultures (PMID: 36734633).	36734633
MDM2 pos TP53 wild-type	triple-receptor negative breast cancer	sensitive	YX-02-030	Preclinical - Cell culture	Actionable	In a preclinical study, YX-02-030 decreased Mdm2 expression, increased apoptosis, decreased survival, and decreased mammosphere formation in TP53 wild-type triple-negative breast cancer cell lines in culture (PMID: 36734633).	36734633
MDM2 pos TP53 R248Q TP53 R267L TP53 R273H	triple-receptor negative breast cancer	sensitive	YX-02-030	Preclinical - Patient cell culture	Actionable	In a preclinical study, YX-02-030 decreased Mdm2 expression and increased apoptosis in patient-derived triple-negative breast cancer explants harboring TP53 R248Q, R267L, and R273H in culture (PMID: 36734633).	36734633
MDM2 pos TP53 R280K	triple-receptor negative breast cancer	sensitive	YX-02-030	Preclinical - Cell line xenograft	Actionable	In a preclinical study, YX-02-030 decreased Mdm2 expression, increased apoptosis, and decreased survival, colony formation, and mammosphere formation in a triple-negative breast cancer cell line harboring TP53 R280K in culture and decreased tumor growth and increased survival in a cell line xenograft model (PMID: 36734633).	36734633
MDM2 pos TP53 D281Y	triple-receptor negative breast cancer	sensitive	YX-02-030	Preclinical - Patient cell culture	Actionable	In a preclinical study, YX-02-030 decreased Mdm2 expression and increased apoptosis in patient-derived triple-negative breast cancer explants harboring TP53 D281Y in culture and increased apoptosis and decreased survival in 3D mammosphere cultures (PMID: 36734633).	36734633