Imlunestrant shows efficacy both with and without abemaciclib

Nature Reviews Clinical Oncology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Language: Английский

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Mitoxantrone inhibits and downregulates ERα through binding at the DBD-LBD interface

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Targeting the estrogen receptor (ER or ERα) through competitive antagonists, downregulators, synthesis inhibition remains primary therapeutic strategy for luminal breast cancer. We have identified a novel mechanism of ER by targeting critical interface between its DNA-binding domain (DBD) and ligand-binding (LBD). demonstrate that mitoxantrone (MTO), topoisomerase II inhibitor, binds at this previously unexplored DBD-LBD interface. Using comprehensive computational, biophysical, biochemical, cellular analyses, we show independent DNA damage response activity, MTO binding induces distinct conformational changes in ER, leading to cytoplasmic redistribution subsequent proteasomal degradation. Notably, effectively inhibits clinically relevant mutations (Y537S D538G) confer resistance current endocrine therapies, outperforming fulvestrant both vitro vivo assays. Our findings establish domain-domain interaction as viable with translational implications other nuclear receptors.

Language: Английский

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Imlunestrant monotherapy improves PFS in ESR1-mutated patients, not in the overall population

Published: Jan. 23, 2025

Language: Английский

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Oral SERDs: Transforming the treatment of advanced breast cancer—Insights from EMBER-3

Med, Journal Year: 2025, Volume and Issue: 6(2), P. 100602 - 100602

Published: Feb. 1, 2025

Language: Английский

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Efficiency of Fulvestrant Monotherapy After CDK4/6 Inhibitor Exposure: Is This a Viable Choice?

Cancers, Journal Year: 2025, Volume and Issue: 17(5), P. 884 - 884

Published: March 4, 2025

Guidelines for the first-line treatment of Hormone Receptor-positive, HER2-negative advanced or recurrent breast cancer have shifted to combination therapies a CDK4/6 inhibitor and endocrine therapy. However, determining an optimal subsequent therapy following progression remains challenging, especially tumors lacking actionable mutations. Real-world data suggest that fulvestrant monotherapy is frequently selected in this post-CDK4/6 setting. This review examines its therapeutic potential evolving landscape. A systematic literature search using PubMed ClinicalTrials.gov identified 153 clinical trials published between 2017 November 2024, from which ten studies met our strict inclusion criteria, focusing solely on monotherapy. These encompassed 1038 patients who had prior exposure inhibitors. The were categorized into three groups: (EMERALD, SERENA-2, AMEERA-3, ELAINE-1), (CAPItello-291 VERONICA), rechallenge (post-MONARCH, PACE, PALMIRA, MAINTAIN). median progression-free survival was 3.18 months (range 1.9–5.3 months). Factors affecting efficacy second-line include treatments, duration, genetic Given short-lived second lines, participating vital option until novel alternative choice becomes available.

Language: Английский

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Oral selective estrogen receptor degraders (SERDs) in Hormone receptor-Positive HER2-Negative Metastatic breast cancer After Progression with CDK4/6 inhibitors

Expert Review of Anticancer Therapy, Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

Hormone receptor-positive (HR+), HER2-negative metastatic breast cancer (mBC) remains a prevalent and challenging disease. Endocrine therapy (ET) combined with CDK4/6 inhibitors is the first-line standard of care, yet resistance mechanisms, including ESR1 mutations, drive disease progression. Novel oral selective estrogen receptor degraders (SERDs) have emerged as promising therapeutic agents after progression secondary to mutations. However, available studies on SERDs differ in design, study population, outcomes, necessitating critical review data. This explores clinical efficacy, safety profiles HR-positive, mBC, particularly following inhibitors. Recent key trials, EMERALD, SERENA-2, EMBER-3 AMEERA-3, are analyzed, highlighting their efficacy overcoming resistance, especially ESR1-mutant populations. Oral offer enhanced bioavailability convenience compared fulvestrant, representing advancement endocrine therapy. Their integration into treatment strategies, combination regimens ctDNA-driven approaches, may improve patient outcomes address mechanisms. other than refinement for selection limited. Further trials needed optimize SERD use define most effective strategies SERDs.

Language: Английский

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Post-Progression treatment options after CDK4/6 inhibitors in hormone Receptor-Positive HER2-Negative metastatic breast cancer

Cancer Treatment Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 102924 - 102924

Published: March 1, 2025

Language: Английский

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Effect of Tasurgratinib as an Orally Available FGFR1–3 Inhibitor on Resistance to a CDK4/6 Inhibitor and Endocrine Therapy in ER+/HER2− Breast Cancer Preclinical Models

Cancers, Journal Year: 2025, Volume and Issue: 17(7), P. 1084 - 1084

Published: March 24, 2025

Fibroblast growth factor (FGF) signaling plays a crucial role in several cellular functions cancer cells. Tasurgratinib, formerly known as E7090, is an orally available FGF receptor (FGFR)1-3 selective inhibitor. Here, we present the effects of tasurgratinib on resistance to CDK4/6 inhibitors and endocrine therapy (ET) preclinical model. Estrogen (ER)+ breast (BC) patient-derived xenograft (PDX) models harboring ESR1 wild-type or mutation were used animal models. An vitro cell proliferation assay ER+ BC lines treated with fulvestrant palbociclib + was conducted presence FGF2 FGF10, without tasurgratinib. Among five PDX models, OD-BRE-0438 OD-BRE-0704 showed higher sensitivities prior than it. In these treatment upregulated expression ligand mRNAs. vitro, FGF10 decreased sensitivity both fulvestrant, which restored by co-treatment Consistently, elacestrant antitumor activity mutation, respectively. ET BC. Tasurgratinib has potential exhibit significant combination against via inhibition. These findings indicate therapeutic treating

Language: Английский

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Potent estrogen receptor β agonists with inhibitory activity in vitro, fail to suppress xenografts of endocrine-resistant cyclin-dependent kinase 4/6 inhibitor-resistant breast cancer cells

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: March 26, 2025

Objective Seventy percent of newly diagnosed breast cancers are estrogen receptor-α positive and HER2/neu negative. First-line treatments incorporate endocrine therapy cyclin-dependent kinase 4/6 inhibitors. However, resistance occurs in most patients. Hence, there is an urgent need for effective second-line treatments. We previously showed that the potent receptor-β agonists, OSU-ERβ-12 LY500307, synergized with selective receptor modulator, tamoxifen, vitro . Furthermore, we these compounds inhibited endocrine-resistant 4/6-inhibitor-resistant α-positive cell lines Here, used fulvestrant- abemaciclib-resistant T47D-derived line xenografts to determine efficacy combination LY500307 tamoxifen vivo Results Despite , failed reduce xenograft tumor volumes. conclude this treatment strategy lacks direct cancer cell-intrinsic cytotoxic

Language: Английский

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Vepdegestrant for the treatment of HR+/HER2– breast cancer

Expert Opinion on Pharmacotherapy, Journal Year: 2025, Volume and Issue: unknown

Published: April 3, 2025

The treatment of advanced hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer has been improved through the development endocrine therapy (ET) targeted agents. However, resistance to ET, particularly caused by ESR1 mutations, not fully addressed. Vepdegestrant is a first-in-class, selective, orally bioavailable PROteolysis TArgeting Chimera (PROTAC) estrogen (ER) degrader. Preclinical studies have suggested promising activity vepdegestrant irrespective genotypes. Phase I II clinical revealed favorable safety profile encouraging efficacy as single agent in combination with other results phase III VERITAC-2 study, comparing fulvestrant, are expected be available 2025, will provide first data on true significance vepdegestrant. Several combinations including + atirimociclib (a cyclin-dependent kinase 4 inhibitor) or planned conducted. these may only transform landscape for HR+/HER2- but pave way PROTAC new class anti-cancer drugs that make previously undruggable targets druggable.

Language: Английский

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