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| Página principal > Artículos > Artículos publicados > Therapy-Induced Senescence Enhances the Efficacy of HER2-Targeted Antibody-Drug Conjugates in Breast Cancer |
(Institut Hospital del Mar d'Investigacions Mèdiques) (Centro de Investigación Biomédica en Red de Cáncer) (Institut Hospital del Mar d'Investigacions Mèdiques) (Centro de Investigación Biomédica en Red de Cáncer) (Centro de Investigación Biomédica en Red de Cáncer) (Centro de Investigación Biomédica en Red de Cáncer) (Vall d'Hebron Institut d'Oncologia) (Vall d'Hebron Institut d'Oncologia) (Vall d'Hebron Institut d'Oncologia) (Vall d'Hebron Institut d'Oncologia) (Instituto de Biología Molecular y Celular del Cáncer (Barcelona)) (Universitat Pompeu Fabra) (Vall d'Hebron Institut d'Oncologia) (Vall d'Hebron Institut d'Oncologia) (Institut Hospital del Mar d'Investigacions Mèdiques) (Institució Catalana de Recerca i Estudis Avançats)| Fecha: | 2022 |
| Resumen: | Antibody-drug conjugates (ADC) are antineoplastic agents recently introduced into the antitumor arsenal. T-DM1, a trastuzumab-based ADC that relies on lysosomal processing to release the payload, is approved for HER2-positive breast cancer. Next-generation ADCs targeting HER2, such as [vic-]trastuzumab duocarmazine (SYD985), bear linkers cleavable by lysosomal proteases and membrane-permeable drugs, mediating a bystander effect by which neighboring antigen-negative cells are eliminated. Many antitumor therapies, like DNA-damaging agents or CDK4/6 inhibitors, can induce senescence, a cellular state characterized by stable cell-cycle arrest. Another hallmark of cellular senescence is the enlargement of the lysosomal compartment. Given the relevance of the lysosome to the mechanism of action of ADCs, we hypothesized that therapies that induce senescence would potentiate the efficacy of HER2-targeting ADCs. Treatment with the DNA-damaging agent doxorubicin and CDK4/6 inhibitor induced lysosomal enlargement and senescence in several breast cancer cell lines. While senescence-inducing drugs did not increase the cytotoxic effect of ADCs on target cells, the bystander effect was enhanced when HER2-negative cells were cocultured with HER2-low cells. Knockdown experiments demonstrated the importance of cathepsin B in the enhanced bystander effect, suggesting that cathepsin B mediates linker cleavage. In breast cancer patient-derived xenografts, a combination treatment of CDK4/6 inhibitor and SYD985 showed improved antitumor effects over either treatment alone. These data support the strategy of combining next-generation ADCs targeting HER2 with senescence-inducing therapies for tumors with heterogenous and low HER2 expression. SIGNIFICANCE: Combining ADCs against HER2-positive breast cancers with therapies that induce cellular senescence may improve their therapeutic efficacy by facilitating a bystander effect against antigen-negative tumor cells. |
| Ayudas: | Ministerio de Economía y Competitividad PT17/0009/0019 Ministerio de Economía y Competitividad AC15/00062 Ministerio de Economía, Industria y Competitividad CB16/12/00449 Instituto de Salud Carlos III PI19/01181 |
| Nota: | Altres ajuts: Breast Cancer Research Foundation (BCRF-20-008) |
| Derechos: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.  |
| Lengua: | Anglès |
| Documento: | Article ; recerca ; Versió publicada |
| Materia: | Antineoplastic Agents ; Breast Neoplasms ; Cathepsin B ; Cell Line, Tumor ; Female ; Humans ; Immunoconjugates ; Receptor, ErbB-2 ; Trastuzumab ; Xenograft Model Antitumor Assays |
| Publicado en: | Cancer research, Vol. 82 Núm. 24 (12 2022) , p. 4670-4679, ISSN 1538-7445 |
