Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer

Muriel Lainé,Marianne E Greene,Bradley Green,Barry Komm,Justyna D Kurleto,Geoffrey L Greene,Ya-Fang Chang,Sean W Fanning,Linda Phung

doi:10.1186/s13058-021-01431-w

Muriel Lainé, Marianne E Greene + Show 7 more

Open Access

https://doi.org/10.1186/s13058-021-01431-w

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Abstract

BackgroundEndocrine therapy remains the mainstay of treatment for estrogen receptor-positive (ER+) breast cancer. Constitutively active mutations in the ligand binding domain of ERα render tumors resistant to endocrine agents. Breast cancers with the two most common ERα mutations, Y537S and D538G, have low sensitivity to fulvestrant inhibition, a typical second-line endocrine therapy. Lasofoxifene is a selective estrogen receptor modulator with benefits on bone health and breast cancer prevention potential. This study investigated the anti-tumor activity of lasofoxifene in breast cancer xenografts expressing Y537S and D538G ERα mutants. The combination of lasofoxifene with palbociclib, a CDK4/6 inhibitor, was also evaluated.MethodsLuciferase-GFP tagged MCF7 cells bearing wild-type, Y537S, or D538G ERα were injected into the mammary ducts of NSG mice (MIND model), which were subsequently treated with lasofoxifene or fulvestrant as single agents or in combination with palbociclib. Tumor growth and metastasis were monitored with in vivo and ex vivo luminescence imaging, terminal tumor weight measurements, and histological analysis.ResultsAs a monotherapy, lasofoxifene was more effective than fulvestrant at inhibiting primary tumor growth and reducing metastases. Adding palbociclib improved the effectiveness of both lasofoxifene and fulvestrant for tumor suppression and metastasis prevention at four distal sites (lung, liver, bone, and brain), with the combination of lasofoxifene/palbociclib being generally more potent than that of fulvestrant/palbociclib. X-ray crystallography of the ERα ligand binding domain (LBD) shows that lasofoxifene stabilizes an antagonist conformation of both wild-type and Y537S LBD. The ability of lasofoxifene to promote an antagonist conformation of Y537S, combined with its long half-life and bioavailability, likely contributes to the observed potent inhibition of primary tumor growth and metastasis of MCF7 Y537S cells.ConclusionsWe report for the first time the anti-tumor activity of lasofoxifene in mouse models of endocrine therapy-resistant breast cancer. The results demonstrate the potential of using lasofoxifene as an effective therapy for women with advanced or metastatic ER+ breast cancers expressing the most common constitutively active ERα mutations.

Highlights

Breast cancer is the most common cause of cancer mortality in women worldwide [1]
Tumor growth with LAS monotherapy Tumors derived from mutant Y537S and D538G cells grew faster than tumors from WT MCF7 cells
In vivo real-time luminescence imaging showed that LAS alone (5 and 10 mg/kg) reduced tumor mass compared with vehicle control in xenograft tumors expressing WT, Y537S, and D538G ERα, similar to FUL (Fig. 1a and Supplementary Figure S2)

Summary

Introduction

Breast cancer is the most common cause of cancer mortality in women worldwide [1]. Approximately 80% of breast cancers are estrogen receptor positive (ER+) [2]. Estradiol (E2) binding to the ER causes receptor dimerization to its active form for coactivator binding, leading to enhanced proliferation and survival of breast epithelial cells through the transcriptional modulation of genes [3, 4]. Endocrine therapy that inhibits ERα activity remains the mainstay of treatment for ER+ breast cancer. Fulvestrant (FUL), the only approved selective estrogen receptor down regulator (SERD), has been shown to be effective in treating endocrine therapy-resistant tumors [8], but the challenges of drug resistance remain even for FUL [9]. Endocrine therapy remains the mainstay of treatment for estrogen receptor-positive (ER+) breast cancer. Breast cancers with the two most common ERα mutations, Y537S and D538G, have low sensitivity to fulvestrant inhibition, a typical second-line endocrine therapy. Lasofoxifene is a selective estrogen receptor modulator with benefits on bone health and breast cancer prevention potential. The combination of lasofoxifene with palbociclib, a CDK4/6 inhibitor, was evaluated

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