Abstract P4-07-01: A small molecule inhibitor (ERX-41) induces endoplasmic reticulum stress in triple negative breast cancer

Autor: RK Vadlamudi, GR Sareddy, Ganesh V. Raj, Mei Kuen Li, Rajeshwar Rao Tekmal, S Ma, J-M Ahn, Mei Zhou, T-K Lee, EM Blatt, Xihui Liu, Suryavathi Viswanadhapalli, Dede N. Ekoue
Rok vydání: 2019
Předmět:
Zdroj: Cancer Research. 79:P4-07
ISSN: 1538-7445
0008-5472
DOI: 10.1158/1538-7445.sabcs18-p4-07-01
Popis: Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer and represents a disproportional share of the breast cancer mortality, primarily due to a lack of targeted therapies. There is a major unmet need for rationally designed novel therapies that can extend survival of patients with TNBC. TNBCs are characterized by a high basal level of endoplasmic reticulum stress, due to high protein turnover and need for proliferation. Recent studies revealed the role of several members of the Nuclear Receptor (NR) superfamily as molecular drivers in TNBC, including the androgen receptor (AR), glucocorticoid receptor (GR) and the orphan NR tailless (TLX). Methods: Recently, using peptidomimetics, we have developed small molecules that specifically target and block interactions of multiple coregulators with oncogenic NRs. We performed a screen of our 500+ compound peptidomimetic library derived from our ERX-11 oligobenzamide (that was rationally designed to target ERα) for anti-proliferative activity in TNBC cell lines. Identified leads were then validated in multiple TNBC cell lines. In vitro activity was tested using Cell titer glo, MTT, matrigel invasion, and apoptosis assays. Mechanistic studies were conducted using Western blot, reporter gene assays, CRISPR/Cas9 KO and RNA-seq analysis. Xenograft, patient derived xenograft (PDX), patient derived explant (PDE) and xenograft derived explant (XDE) TNBC models were used for preclinical evaluation and toxicity. Results: We have identified a first-in-class drug (ERX-41) that has potent activity (IC50 = 50-250nM) against all six molecular subtypes of TNBC. Systematic evaluation using CRISPR/Cas9 KO screen and overexpression screen comprising 48 NRs identified TLX as a preferred target of ERX-41. Analyses of primary breast tumors revealed TLX was highly expressed in TNBC. Further, TLX was amplified in nearly 50% of TNBC xenografts (cbioportal.org). Modelling, mechanistic and biochemical studies showed that ERX-41 interact with TLX and selectively blocks its interactions with coregulators. Gene expression analyses revealed both significant reduction of TLX-activated genes (CCND1, WNT7A) and significant activation of TLX-repressed genes (p21) upon treatment with ERX-41 in TNBC models. Gene ontogeny pathway analyses of RNA-seq data in TNBC cells showed that ERX-41 treatment positively correlated with apoptosis. Our ultrastructural studies indicated that ERX-41 enhances endoplasmic reticulum stress in TNBC inducing autophagic flux and subsequent apoptosis. ERX-41 has significant potency against multiple TNBC xenografts and PDXs in vivo, PDEs and XDEs ex vivo, indicating its potential for clinical translation. Pharmacologically, ERX-41 exhibited high oral bioavailability and associated with minimal toxicity upon oral gavage for up to 120 days in animal studies. Conclusions: We believe that the ability of ERX-41 to block NR signaling and target a critical molecular vulnerability in TNBC and its ability to enhance endoplasmic reticulum stress in TNBC, will revolutionize the therapeutic landscape of TNBC. ERX-41 is oral bioavailable, potent against multiple TNBC molecular subtypes, and is associated with minimal systemic side effects. (supported by NIH grant RO1 CA223828-01) Citation Format: Liu X, Viswanadhapalli S, Ma S, Lee T-K, Sareddy GR, Ekoue DN, Blatt EM, Zhou M, Li M, Tekmal RR, Ahn J-m, Vadlamudi RK, Raj GV. A small molecule inhibitor (ERX-41) induces endoplasmic reticulum stress in triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-07-01.
Databáze: OpenAIRE
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