Combined Targeting of Estrogen Receptor Alpha and XPO1 Prevent Akt Activation, Remodel Metabolic Pathways and Induce Autophagy to Overcome Tamoxifen Resistance.

Eylem Kulkoyluoglu-Cotul,Karen Lee Ann Chen,Hua Chang,Yiru Chen Zhao,Barbara Haley,Yosef Landesman,Zeynep Madak-Erdogan,Sunati Sahoo,Aditi Mehta,Kinga Wrobel,Kadriye Hieronymi,Ozan Berk Imir,Caitlin O'Callaghan,Kevin Duong,Brandi Patrice Smith

doi:10.3390/cancers11040479

Abstract

A majority of breast cancer specific deaths in women with ERα (+) tumors occur due to metastases that are resistant to endocrine therapy. There is a critical need for novel therapeutic approaches to resensitize recurrent ERα (+) tumors to endocrine therapies. The objective of this study was to elucidate mechanisms of improved effectiveness of combined targeting of ERα and the nuclear transport protein XPO1 in overcoming endocrine resistance. Selinexor (SEL), an XPO1 antagonist, has been evaluated in multiple late stage clinical trials in patients with relapsed and/or refractory hematological and solid tumor malignancies. Our transcriptomics analysis showed that 4-Hydroxytamoxifen (4-OHT), SEL alone or their combination induced differential Akt signaling- and metabolism-associated gene expression profiles. Western blot analysis in endocrine resistant cell lines and xenograft models validated differential Akt phosphorylation. Using the Seahorse metabolic profiler, we showed that ERα-XPO1 targeting changed the metabolic phenotype of TAM-resistant breast cancer cells from an energetic to a quiescent profile. This finding demonstrated that combined targeting of XPO1 and ERα rewired the metabolic pathways and shut down both glycolytic and mitochondrial pathways that would eventually lead to autophagy. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and given the need for better strategies to improve therapy response in relapsed ERα (+) tumors, our findings show great promise for uncovering the role that ERα-XPO1 crosstalk plays in reducing cancer recurrences.

Highlights

The nuclear hormone receptor estrogen receptor alpha (ERα) is present in approximately 70%of both early and late stage human breast cancers [1,2]
We demonstrated that combined targeting of XPO1 and ERα in TAM-resistant cell lines shuts down metabolic pathways that would eventually lead to autophagy
Our studies provide a novel mechanism of action of combined targeting of ERα and XPO1 to overcome TAM resistance in recurrent ERα (+) breast cancer

Summary

Introduction

The nuclear hormone receptor estrogen receptor alpha (ERα) is present in approximately 70%of both early and late stage human breast cancers [1,2]. ERα is targeted by endocrine therapies that are well tolerated and provide long-term disease-free survival if patients have localized disease [1]. 30% of patients with ER positive (ER (+)) disease experience recurrence and metastasis, and there is a consistent long-term risk of death due to recurrent breast cancer with an even greater risk after 7 years [3,4,5,6,7]. These are not optimal in terms of pharmacological properties due to poor tolerance and side effects that decrease the quality of the patient’s life. Many patients with ER (+) tumors will continue to face diminished prospects for long-term survival being prescribed regimens that decrease their quality of life without receiving clinical benefit

Objectives

Methods

Findings

Discussion

Conclusion