# Effect of CX4945 in tamoxifen resistant BCa

> **NIH NIH SC1** · XAVIER UNIVERSITY OF LOUISIANA · 2022 · $284,000

## Abstract

Non-genomic estrogen signaling has been implicated in mediating therapeutic resistance to anti-estrogen
therapies in breast carcinoma (BCa) and may contribute to the mitogenic effects of selective estrogen receptor
modulators (SERMS). ERα36 [a 36 Kd transcript variant of estrogen receptor alpha (ERα)] mediates non-
genomic estrogen signaling, and is implicated in anti-estrogen resistance and anti-estrogen induced
mitogenesis1. Dual inhibition of ERα66 (full length ERα) and ERα36 signaling might prove to be a more
efficacious mode of antihormonal therapy that avoids the acquisition of anti-estrogen induced resistance and
tumorigenesis. This can be achieved by pharmacological targeting of the common posttranslational regulatory
mechanisms (ie, phosphorylation) between the two isoforms. CX4945 (silmitasertib), a clinical stage CK2
inhibitor, represses protein levels of both ERα66 and ERα36. As such CX4945 might serve to uniquely disrupt
oncogenic kinase signaling as well as reduces stability of ERα isoforms in BCa. We hypothesize that CX4945
inhibits both genomic and nongenomic estrogenic signaling by functioning as an indirect pan-estrogen receptor
downregulator which disrupts both ERα66 and ERα36 expression in BCa.
In order to test this hypothesis we will:
Aim I. Investigate the role of the ERα66/36 /CK2 signaling axis in the development of tamoxifen resistance.
For this aim we hypothesize that CK2 promotes the development of 4HT resistance by promoting aberrant ERα
signaling. We will determine the incidence and causative role of altered ERα36 and CK2 expression in the
development of tamoxifen resistance in breast cancer.
Aim 2 Elucidate the mechanisms of CX4945 mediated downregulation of ERα66/36 in BCa. Here we
hypothesize that pharmacological inhibition of CK2 with CX4945 renders ERα isoforms susceptible to the 26S
proteasomal degradation pathway. We will ascertain the impact of CK2 mediated phosphorylation of ERα66/36 on
chaperone interaction, ubiquitination and subsequently the proteolytic degradation of ERα36.
Aim 3 Assess the antineoplastic efficacy of CX4945 in paired patient derived xenograft (PDX) models of
4HT sensitive and resistant models of BCa. We hypothesize that CX4945 will inhibit the progression of
tamoxifen-sensitive and tamoxifen-resistant (de novo and acquired) PDX tumors. PDX tumors from endocrine
sensitive patients will be used to generate models of acquired resistance, whereas de-novo resistance will be
modelled using PDX from patients with Y537S mutation.
The successful completion of these studies could lead to the use of CX4945 or similar CK2 inhibitors with indirect
pan-ERα downregulating functions in the treatment of hormone sensitive and hormone resistant breast cancer.

## Key facts

- **NIH application ID:** 10458662
- **Project number:** 5SC1GM136562-03
- **Recipient organization:** XAVIER UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Christopher Williams
- **Activity code:** SC1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $284,000
- **Award type:** 5
- **Project period:** 2020-08-05 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10458662

## Citation

> US National Institutes of Health, RePORTER application 10458662, Effect of CX4945 in tamoxifen resistant BCa (5SC1GM136562-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10458662. Licensed CC0.

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