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

Abstract

Background Endocrine 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. Methods Luciferase-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. Results As 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. Conclusions We 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.

Stereo-specific Lasofoxifene Derivatives Reveal the Interplay between Estrogen Receptor Alpha Stability and Antagonistic Activity in ESR1 Mutant Breast Cancer Cells

“…Likewise, the RU39411 structures show similar H12 conformational changes with H12 moving closer to the AF2 cleft in the Y537S vs WT (Figure 7C). We previously observed similar WT and Y537S structures for lasofoxifene, which also maintains significant transcriptional inhibitory activities 28 . For LA-Deg, its 3R-methylpyrrolidine points towards the H11-12 loop and H12 is less ordered, similar to other SERDs 26 .…”

“…Importantly, we also showed that enforcing H12 burial in the AF-2 cleft improves transcriptional antagonistic activities on a reporter vector in breast cancer cells harboring WT/Y537S ESR1. Our studies, combined with the recent work from the McDonnell Laboratory showing that transcriptional antagonism contributes most of fulvestrant's therapeutic activities independent of maximal receptor depletion 31 , and the observed significant efficacy of the SERM/SERD lasofoxifene for the Y537S mutant 28 , suggest that future antiestrogen development efforts for treatment of tumors with constitutively active mutations should focus on maximizing transcriptional antagonistic activities.…”

“…Antiestrogens with improved potencies including bazedoxifene, fulvestrant, OP-1074 and GDC-0945 possess variable degrees of ERα degrading/downregulating activities but show significant potencies and efficacies in mutant ESR1 breast cancer cells 5,25,26 . Initial studies suggested that SERD activity was necessary for therapeutic potency 5 ; however, Lainé et al also showed that the SERM lasofoxifene induced marked anti-cancer activities in xenografts of Y537S ESR1 breast cancer cells without fulvestrant-level ERα degradation 28 . In addition, Wardell et al showed that antagonism rather than ERα degradation/downregulation drives fulvestrant efficacy 31 .…”

“…Recent studies suggest that ERα degrading activities may not be required for therapeutic efficacy in breast cancer cells with recurring hotspot ESR1 mutations. Next generation antiestrogens with mixed SERM/SERD activities including bazedoxifene and lasofoxifene, which possess weaker ERα degrading/downregulating activities, show potent anti-cancer activities in breast cancers harboring ESR1muts 13,[28][29][30] . In addition, mutations abolishing induction of receptor SUMOylation reduced but did not abolish transcriptional suppression by fulvestrant in breast cancer cells 16 .…”

The BA-BCS 2021: An Initial “Trial” for Integrating Basic Science and Medical Progress on Breast Cancer in a Latin-American Country

“…He then moved on to his recent and novel discoveries of ESR1 mutations in metastatic breast cancers [ 4 ] and the use of new selective estrogen receptor modulators (SERMs) to target them. He also showed data from the mammary intraductal model (MIND), a variant of the patient-derived xenograft (PDX) animal model that has led to new clinical trials of lasofoxifene [ 5 ]. In addition, he is currently studying the potential protective benefit of a recently approved hormone replacement therapy that combines an estrogen with a SERM.…”