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

• Published in: Breast cancer research : BCR Vol. 23; no. 1; p. 54
• Main Authors: Lainé, Muriel, Fanning, Sean W, Chang, Ya-Fang, Green, Bradley, Greene, Marianne E, Komm, Barry, Kurleto, Justyna D, Phung, Linda, Greene, Geoffrey L
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 12.05.2021; BioMed Central; BMC
• Subjects: 60 APPLIED LIFE SCIENCES; Animal models; Animals; Antibodies; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Antitumor agents; Bioavailability; Bone cancer; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cancer therapies; Cardiovascular disease; Conformation; Crystallography; Cyclin-dependent kinase 4; Cytokeratin; Disease Models, Animal; Drug dosages; Endocrine resistant; Endocrine therapy; Estrogen; Estrogen Receptor alpha - antagonists & inhibitors; Estrogen Receptor alpha - chemistry; Estrogen Receptor alpha - genetics; Estrogen receptors; Estrogens; Female; Fulvestrant; Fulvestrant - therapeutic use; Genetic aspects; Humans; Laboratories; Lasofoxifene; Ligands; Lungs; MCF-7 Cells; Metastases; Metastasis; Mice; Mutation; Neoplasm Metastasis - prevention & control; Neuroimaging; Oncology, Experimental; Osteoporosis; Piperazines - therapeutic use; Prevention; Protein Binding; Protein Conformation; Protein Kinase Inhibitors - therapeutic use; Pyridines - therapeutic use; Pyrrolidines - chemistry; Pyrrolidines - therapeutic use; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; Selective estrogen receptor modulator; Selective Estrogen Receptor Modulators - chemistry; Selective Estrogen Receptor Modulators - therapeutic use; Software; Tetrahydronaphthalenes - chemistry; Tetrahydronaphthalenes - therapeutic use; Treatment Outcome; Tumor suppression; Tumors; Womens health; X-ray crystallography; Xenografts; Endocrine resistant; Breast cancer; Selective estrogen receptor modulator; Lasofoxifene; Fulvestrant
• ISSN: 1465-542X; 1465-5411; 1465-542X
• DOI: 10.1186/s13058-021-01431-w

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. 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. 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. 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.