Antibody-drug conjugates in breast cancer treatment: resistance mechanisms and the role of therapeutic sequencing

Cancer Drug Resistance, Journal Year: 2025, Volume and Issue: unknown

Published: March 6, 2025

Antibody-drug conjugates (ADCs) are a transformative approach in breast cancer therapy, offering targeted treatment with reduced toxicity by selectively delivering cytotoxic agents to cells. While ADCs like trastuzumab emtansine (T-DM1), deruxtecan (T-DXd), and sacituzumab govitecan have shown significant efficacy, resistance mechanisms such as antigen loss, impaired internalization, efflux of payloads challenge their effectiveness. This review discusses these explores advanced strategies overcome them, including innovations linker chemistry, multi-antigen targeting, biomarker-driven personalization. Additionally, therapeutic sequencing - determining the optimal order other treatments chemotherapy, endocrine immunotherapy is examined crucial maximize ADC efficacy manage resistance. Evidence-based strategies, particularly for human epidermal growth factor receptor 2 (HER2)-positive triple-negative (TNBC), supported clinical trials demonstrating benefits both early-stage metastatic settings. The potential combination therapies, immune checkpoint inhibitors (ICIs), further highlights evolving landscape treatment. As technology advances, personalized approaches integrating biomarkers optimized protocols offer promising avenues enhance outcomes combat cancer.

Language: Английский

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Antibody-drug conjugates in breast cancer: current evidence and future directions

Experimental Hematology and Oncology, Journal Year: 2025, Volume and Issue: 14(1)

Published: March 20, 2025

Abstract Antibody-drug conjugates (ADCs) are a rapidly evolving class of antitumor drugs and have already revolutionized the treatment strategy many hematologic solid cancers. So far, trastuzumab emtansine (T-DM1), deruxtecan (T-DXd), sacituzumab govitecan (SG) datopotamab (Dato-DXd) four ADCs that been approved by US food drug administration (FDA) in breast cancer, SKB264 has Chinese national medical products (NMPA). Many for cancer currently being tested late-phase clinical trials, with several encouraging results achieved recently. However, major issues arise during use ADCs, including emergence acquired resistance, occurrence treated-related toxicities, identification biomarkers response resistance. increasingly combination other agents, novel next-generation ADC development is progressing rapidly. A better understanding design will promote treatment. In this review, we aim to provide broad overview recent advances cancer. We also propose notable future directions

Language: Английский

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Diagnostic and therapeutic advances for HER2-expressing or amplified gynecologic cancers

Gynecologic Oncology, Journal Year: 2025, Volume and Issue: 195, P. 152 - 164

Published: March 21, 2025

HER2-targeting therapies are well-described in breast, gastric, and lung cancers, however accumulating data supports a role for HER2-targeted gynecologic cancers. Despite varied methodologies HER2 testing, evidence that substantial proportion of endometrial, ovarian, cervical, vulvar cancers overexpress HER2. This underscores the rationale these malignancies, including use HER2-directed tyrosine kinase inhibitors, antibody-drug conjugates, immune-stimulating antibody conjugates. Understanding mechanisms resistance to will inform possible combinatorial strategies.

Language: Английский

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Multi-omic profiling in breast cancer: utility for advancing diagnostics and clinical care

Expert Review of Molecular Diagnostics, Journal Year: 2025, Volume and Issue: unknown

Published: April 7, 2025

Breast cancer remains a major global health challenge. While advances in precision oncology have contributed to improvements patient outcomes and provided deeper understanding of the biological mechanisms that drive disease, historically, research patients' allocation treatment heavily relied on single-omic approaches, analyzing individual molecular dimensions such as genomics, transcriptomics, or proteomics. these deep insights into breast biology, they often fail offer complete disease's complex landscape. In this review, authors explore recent advancements multi-omic realm using clinical data show how integration can more holistic alterations their functional consequences underlying cancer. The overall developments AI are expected complement diagnostics through potentially refining prognostic models, selection. Overcoming challenges cost, complexity, lack standardization is crucial for unlocking full potential multi-omics care enable advancement personalized treatments improve outcomes.

Language: Английский

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SNX10 deficiency impairs sensitivity to anti-HER2 antibody–drug conjugates via altering HER2 trafficking in HER2-positive breast cancer

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(16)

Published: April 14, 2025

Antibody–drug conjugates (ADCs) are a rapidly developing therapeutic approach in cancer treatment that has shown remarkable efficacy breast cancer. Despite the promising of anti-HER2 ADCs, many patients still experiencing disease progression under treatment. Here, by analyzing transcriptome data from patient-derived organoid models, I-SPY2 trial, and resistant cell lines, we identified SNX10 deficiency conferred ADCs resistance HER2-positive Low levels attenuated HER2 recycling promoted trafficking into lysosomes. Furthermore, found underlying mechanism traffic regulating endosomal RAB11A. We propose contributes to inhibition as well decrease cell-surface causes ADC resistance.

Language: Английский

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Current progress and remaining challenges of peptide–drug conjugates (PDCs): next generation of antibody-drug conjugates (ADCs)?

Journal of Nanobiotechnology, Journal Year: 2025, Volume and Issue: 23(1)

Published: April 22, 2025

Drug conjugates have emerged as a promising alternative delivery system designed to deliver an ultra-toxic payload directly the target cancer cells, maximizing therapeutic efficacy while minimizing toxicity. Among these, antibody-drug (ADCs) garnered significant attention from both academia and industry due their great potential for therapy. However, peptide-drug (PDCs) offer several advantages over ADCs, including more accessible industrial synthesis, versatile functionalization, high tissue penetration, rapid clearance with low immunotoxicity. These factors position PDCs up-and-coming drug candidates future Despite potential, face challenges such poor pharmacokinetic properties bioactivity, which hinder clinical development. How design meet needs is big challenge urgent resolve. In this review, we first carefully analyzed general consideration of successful PDC learning ADCs. Then, summarised basic functions each component construct, comprising peptides, linkers payloads. The peptides in were categorized into three types: tumor targeting cell penetrating peptide self-assembling peptide. We then these delivery, overcoming resistance, controlling release improving reduced non-specific To better understand druggability PDCs, discussed pharmacokinetics also briefly introduced current trials. Lastly, perspectives development oncology PDC. This review aimed provide useful information construction applications.

Language: Английский

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MUC1-C dependency in drug resistant HR+/HER2− breast cancer identifies a new target for antibody-drug conjugate treatment

npj Breast Cancer, Journal Year: 2025, Volume and Issue: 11(1)

Published: April 26, 2025

Abstract Treatment of hormone receptor (HR)-positive, HER2-negative breast cancer (HR+/HER2− BC) is limited by resistance to endocrine therapy (ET) and CDK4/6 inhibitors. There no known common pathway that confers these agents. We report (i) the MUC1 gene upregulated in HR+/HER2− BCs (ii) MUC1-C protein regulates estrogen alpha (ER)-driven transcriptomes. Mechanistically, we demonstrate necessary for expression SRC-3 MED1 coactivators drive ER-mediated target transcription. Cells with ESR1 mutations confer ET resistance, as well cells acquired inhibitor abemaciclib, are dependent on ER genes, survival, (iii) self-renewal capacity. In support results, show treatment BC an anti-MUC1-C antibody-drug conjugate (ADC) effectively inhibits tumorgenicity. These findings indicate a effector drug-resistant potential their treatment.

Language: Английский

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Antibody-drug conjugate components in association with the incidence of ADC-related interstitial lung disease: A systematic review and meta‐analysis

Lung Cancer, Journal Year: 2025, Volume and Issue: unknown, P. 108559 - 108559

Published: April 1, 2025

Language: Английский

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Present and Future of Immunotherapy for Triple-Negative Breast Cancer

Published: Aug. 14, 2024

Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptors, human epidermal growth factor receptor 2, and progesterone receptors (PR). TNBC has poorest prognosis among subtypes is more likely to respond immunotherapy due its higher PD-L1 a greater percentage tumor-infiltrating lymphocytes. Immunotherapy revolutionized treatment, especially with FDA's approval pembrolizumab (Keytruda) combined chemotherapy for advanced cases, opening new avenues treating this deadly disease. Although, can significantly improve patient outcomes in subset patients, achieving desired response rate all remains an unmet clinical goal. Strategies that responses immune checkpoint blockade, including combining chemotherapy, molecularly targeted therapy, or radiotherapy may rates outcomes. In review, we provide short background on explore different types strategies are currently being evaluated TNBC. Additionally, review why combination be beneficial, overview strategies, discuss novel immunotherapeutic opportunities approved near future

Language: Английский

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Antibody-Drug Conjugates: The New Treatment Approaches for Ovarian Cancer

Cancers, Journal Year: 2024, Volume and Issue: 16(14), P. 2545 - 2545

Published: July 15, 2024

Ovarian cancer (OC), accounting for approximately 200,000 deaths worldwide annually, is a heterogeneous disease showing major differences in terms of its incidence, tumor behavior, and outcomes across histological subtypes. In OC, primary chemotherapy, paclitaxel carboplatin, bevacizumab, PARP inhibitors have shown prolonged progression-free survival favorable overall response rate compared to conventional treatments. However, treatment options platinum-resistant recurrence cases are limited, with no effective therapies that significantly prolong the prognosis. Recently, mirvetuximab soravtansine, an alpha-folate receptor (FRα)-targeted antibody-drug conjugate (ADC), was approved by US Food Drug Administration patients FRα-positive recurrent epithelial OC (EOC). This approval based on Phase II study, which demonstrated efficacy such patients. ADCs comprise antibody, linker, payload, representing new concept agents without precedence. Advanced clinical studies developing targeting solid tumors as gynecologic cancer. Ongoing trials evaluating FRα human epidermal growth factor 2, trophoblast cell surface antigen-2, sodium-dependent phosphate transport protein 2B, cadherin-6 II/III studies. this review, we summarize existing evidence supporting use discuss ongoing preclinical studies, explore potential these innovative address challenges treatment.

Language: Английский

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