mTOR inhibition and trastuzumab-emtansine (T-DM1) in HER2-positive breast cancer
| Autor: | Casadevall D, Hernandez-Prat A, Garc A-Alonso S, Arpi-Llucia O, Menendez S, Qin M, Guardia C, Morancho B, Sanchez-Mart N F, Zazo S, Gavilan E, Sabbaghi M, Eroles P, Cejalvo J, Lluch A, Rojo F, Pandiella A, Rovira A, Albanell J |
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| Rok vydání: | 2022 |
| Zdroj: | Molecular cancer research : MCR r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA instname |
| ISSN: | 1557-3125 |
| Popis: | 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-DM1 levels, 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 PDX-derived 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. Implications: Inhibition of mTOR increases the anti-tumor activity of T-DM1, supporting that the combination of mTOR inhibitors and antibody-drug conjugates warrants clinical evaluation in patients with HER2-positive breast cancer. |
| Databáze: | OpenAIRE |
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