Reference Detail

Ref Type

Journal Article

PMID

(31488700)

Authors

Capasso A, Bagby SM, Dailey KL, Currimjee N, Yacob BW, Ionkina A, Frank JG, Kim DJ, George C, Lee YB, Benaim E, Gittleman B, Hartman SJ, Tan AC, Kim J, Pitts TM, Eckhardt SG, Tentler JJ, Diamond JR

Title

First-in-Class Phosphorylated-p68 Inhibitor RX-5902 Inhibits β-Catenin Signaling and Demonstrates Antitumor Activity in Triple-Negative Breast Cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	18	11	2019 11	1916-1925	Mol Cancer Ther

URL

Abstract Text

RX-5902 is a first-in-class anticancer agent targeting phosphorylated-p68 and attenuating nuclear shuttling of β-catenin. The purpose of this study was to evaluate the efficacy of RX-5902 in preclinical models of triple-negative breast cancer (TNBC) and to explore effects on β-catenin expression. A panel of 18 TNBC cell lines was exposed to RX-5902, and changes in proliferation, apoptosis, cellular ploidy, and effector protein expression were assessed. Gene expression profiling was used in sensitive and resistant cell lines with pathway analysis to explore pathways associated with sensitivity to RX-5902. The activity of RX-5902 was confirmed in vivo in cell line and patient-derived tumor xenograft (PDX) models. RX-5902 demonstrated potent antiproliferative activity in vitro against TNBC cell lines with an average IC50 of 56 nmol/L in sensitive cell lines. RX-5902 treatment resulted in the induction of apoptosis, G2-M cell-cycle arrest, and aneuploidy in a subset of cell lines. RX-5902 was active in vivo against TNBC PDX models, and treatment resulted in a decrease in nuclear β-catenin. RX-5902 exhibited dose-proportional pharmacokinetics and plasma and tumor tissue in nude mice. Pathway analysis demonstrated an increase in the epithelial-to-mesenchymal transformation (EMT), TGFβ, and Wnt/β-catenin pathways associated with sensitivity to RX-5902. RX-5902 is active against in vitro and in vivo preclinical models of TNBC. Target engagement was confirmed with decreases in nuclear β-catenin and MCL-1 observed, confirming the proposed mechanism of action. This study supports the continued investigation of RX-5902 in TNBC and combinations with immunotherapy.

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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
RX-5902	RX-5902	0	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
RX-5902		Supinoxin	CTNNB1 Inhibitor 27	Supinoxin (RX-5902) binds to and inhibits Ddx5, which in turn inhibits beta-catenin signaling, results in down-regulation of gene expression and tumor cell growth inhibition (PMID: 25649741, PMID: 31488700).

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