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

Abstract

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.

• Authors: Anna Capasso, Stacey M Bagby, Kyrie L Dailey, Naomi Currimjee, Betelehem W Yacob, Anastasia Ionkina, Julie G Frank, Deog Joong Kim, Christina George, Young B Lee, Ely Benaim, Brian Gittleman, Sarah J Hartman, Aik Choon Tan, Jihye Kim, Todd M Pitts, S Gail Eckhardt, John J Tentler, Jennifer R Diamond
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 18 Issue 11 Pg. 1916-1925 (11 2019) ISSN: 1538-8514 [Electronic] United States
• PMID: 31488700 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• CTNNB1 protein, human
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Piperazines
• Quinoxalines
• RX-5902
• beta Catenin
• eIF-2 Kinase

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mice
• Myeloid Cell Leukemia Sequence 1 Protein (metabolism)
• Phosphorylation
• Piperazines (administration & dosage, pharmacology)
• Quinoxalines (administration & dosage, pharmacology)
• Triple Negative Breast Neoplasms (drug therapy, metabolism)
• Wnt Signaling Pathway (drug effects)
• Xenograft Model Antitumor Assays
• beta Catenin (metabolism)
• eIF-2 Kinase (metabolism)