# Targeting Aurora-A Kinase to Overcome Endocrine Resistance in ER+ Breast Cancer

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $324,060

## Abstract

ABSTRACT
De novo or acquired resistance to endocrine therapy is a key driver of relapse and tumor progression in
patients with estrogen receptor (ER+) breast cancer. Downregulation of the ERα is a well-established yet
poorly understand mechanism of endocrine resistance. Currently there are no approved or investigational
therapies that can restore ERα expression after downregulation occurs. Our preclinical research was the first
to demonstrate in luminal ER+ breast cancer a novel role of Aurora-A kinase (AURKA) in the induction of
stemness reprogramming and expansion of a sub-population of CD44high/CD24low breast tumor initiating cells
(BTICs). These BTICs have low ERα expression and are resistant to endocrine therapy. They are further
characterized by stem cell-like phenotype that mediates tumor properties of invasion, self-renewal, drug
resistance, and metastasis. We propose in ER+ breast cancer that activation of AUKRA induces expansion of
BTICs during tumor progression that drives ERα downregulation and endocrine resistance.
When BTICs are treated with the selective AURKA inhibitor, alisertib, the luminal phenotype, ERα expression
and endocrine sensitivity are restored. Our preclinical data demonstrates synergy when alisertib is combined
with fulvestrant in endocrine resistant models. We have recently determined the maximum tolerated dose of
alisertib in combination with standard dose fulvestrant in a phase I clinical trial in advanced ER+ breast cancer.
An excellent safety profile and impressive 6-month clinical benefit rate of 78% were observed.
The objective of the proposed research is to explore in preclinical models and clinical biospecimens the
molecular mechanisms by which AURKA promotes endocrine resistance through stemness reprogramming
and downregulation of ERα. Our central hypothesis is that alisertib selectively targets BTICs and converts
them to a CD44low/CD24high luminal phenotype with increased ERα expression and sensitivity to endocrine
therapy. The following Aims will assess the central hypothesis: In Specific Aim 1 we will evaluate AURKA as a
novel biomarker and therapeutic target in endocrine resistant, metastatic breast cancer. In Specific Aim 2 we
will determine in vivo the mechanisms underlying AURKA-induced endocrine resistance and tumor
progression. In Specific Aim 3 we will define the role of SMAD5/SOX2 transcriptional network in mediating
AURKA-induced enrichment of CD44high/CD24low/ERαlow BTICs.
Dissecting the mechanisms by which AURKA induces stemness reprogramming is of high translational
significance because AURKA inhibitors may represent a novel therapeutic approach to address de novo and
acquired endocrine resistance due to ERα downregulation. The proposed research will establish the extent to
which targeting AURKA has consequent benefit to delay or prevent tumor progression and improve the survival
of patients with ER+ breast cancer. This research is directly relevant to the goals of the NIH because it will
enh...

## Key facts

- **NIH application ID:** 9940698
- **Project number:** 5R01CA214893-04
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Antonio BONAVENTURA D'Assoro
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $324,060
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9940698

## Citation

> US National Institutes of Health, RePORTER application 9940698, Targeting Aurora-A Kinase to Overcome Endocrine Resistance in ER+ Breast Cancer (5R01CA214893-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9940698. Licensed CC0.

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