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Título: | mTOR Inhibition and T-DM1 in HER2-Positive Breast Cancer |
Autor: | Casadevall, David; Hernández-Prat, Anna; García-Alonso, Sara; Menendez, Silvia; Qin, Mengjuan; Guardia, Cristina; Morancho, B.; Sánchez-Martín, Francisco Javier; Zazo, Sandra; Gavilán, Elena CSIC ORCID; Sabbaghi, Mohammad A.; Eroles, Pilar; Cejalvo, Juan Miguel; Lluch, Ana; Rojo, Federico; Pandiella, Atanasio CSIC ORCID CVN ; Rovira, Ana; Albanell, Joan | Fecha de publicación: | jul-2022 | Editor: | American Association for Cancer Research | Citación: | Molecular Cancer Research 20(7): 1108-1121 (2022) | Resumen: | In patients with trastuzumab-resistant HER2-positive breast cancer, the combination of everolimus (mTORC1 inhibitor) with trastuzumab failed to show a clinically significant benefit. However, the combination of mTOR inhibition and the antibody-drug conjugate (ADC) trastuzumab-emtansine (T-DM1) remains unexplored. We tested T-DM1 plus everolimus in a broad panel of HER2-positive breast cancer cell lines. The combination was superior to T-DM1 alone in four cell lines (HCC1954, SKBR3, EFM192A, and MDA-MB-36) and in two cultures from primary tumor cells derived from HER2-positive patient-derived xenografts (PDX), but not in BT474 cells. In the trastuzumab-resistant HCC1954 cell line, we characterized the effects of the combination using TAK-228 (mTORC1 and -2 inhibitor) and knockdown of the different mTOR complex components. T-DM1 did not affect mTOR downstream signaling nor induct autophagy. Importantly, mTOR inhibition increased intracellular T-DM1levels, leading to increased lysosomal accumulation of the compound. The increased efficacy of mTOR inhibition plus T-DM1 was abrogated by lysosome inhibitors (chloroquine and bafilomycin A1). Our experiments suggest that BT474 are less sensitive to T-DM1 due to lack of optimal lysosomal processing and intrinsic resistance to the DM1 moiety. Finally, we performed several in vivo experiments that corroborated the superior activity of T-DM1 and everolimus in HCC1954 and PDXderived mouse models. In summary, everolimus in combination with T-DM1 showed strong antitumor effects in HER2-positive breast cancer, both in vitro and in vivo. This effect might be related, at least partially, to mTOR-dependent lysosomal processing of T-DM1, a finding that might apply to other ADCs that require lysosomal processing. | Versión del editor: | http://dx.doi.org/10.1158/1541-7786.MCR-21-0545 | URI: | http://hdl.handle.net/10261/282954 | DOI: | 10.1158/1541-7786.MCR-21-0545 | Identificadores: | doi: 10.1158/1541-7786.MCR-21-0545 issn: 1541-7786 e-issn: 1557-3125 |
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