First-in-class phosphorylated-p68 inhibitor RX-5902 inhibits β-catenin signaling and demonstrates anti-tumor activity in triple-negative breast cancer

• Published in: Molecular cancer therapeutics Vol. 18; no. 11; pp. 1916 - 1925
• Main Authors: Capasso, Anna, Bagby, Stacey M., Dailey, Kyrie L., Currimjee, Naomi, Yacob, Betelehem W., Ionkina, Anastasia, Frank, Julie G., Kim, Deog Joong, George, Christina, Lee, Young B., Benaim, Ely, Gittleman, Brian, Hartman, Sarah J., Tan, Aik Choon, Kim, Jihye, Pitts, Todd M, Eckhardt, S. Gail, Tentler, John J., Diamond, Jennifer R.
• Format: Journal Article
• Language: English
• Published: 05.09.2019
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-18-1334

RX-5902 is a first-in-class anti-cancer 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 TNBC and to explore effects on β-catenin expression. A panel of 18 TNBC cell lines were 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 IC 50 of 56 nM 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 EMT, TGF beta, 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.