mTOR inhibition and T-DM1 in HER2-positive breast cancer

Mostra el registre complet Registre parcial de l'ítem

  • dc.contributor.author Casadevall Aguilar, David
  • dc.contributor.author Hernández Prat, Anna, 1984-
  • dc.contributor.author García-Alonso, Sara
  • dc.contributor.author Arpí Llucià, Oriol
  • dc.contributor.author Menéndez, Silvia
  • dc.contributor.author Qin, Mengjuan
  • dc.contributor.author Guardia Valenzuela, Cristina, 1990-
  • dc.contributor.author Morancho Armisen, Beatriz
  • dc.contributor.author Sánchez-Martín, Francisco Javier
  • dc.contributor.author Zazo, Sandra
  • dc.contributor.author Gavilán, Elena
  • dc.contributor.author Sabbaghi Mehrjardi, Mohammad Ali
  • dc.contributor.author Eroles, Pilar
  • dc.contributor.author Cejalvo, Juan M.
  • dc.contributor.author Lluch, Ana
  • dc.contributor.author Rojo, Federico
  • dc.contributor.author Pandiella, Atanasio
  • dc.contributor.author Rovira, Ana
  • dc.contributor.author Albanell Mestres, Joan
  • dc.date.accessioned 2022-10-19T06:33:13Z
  • dc.date.issued 2022
  • dc.description.abstract 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.
  • dc.description.sponsorship This work was supported by ISCIII (CIBERONC CB16/12/00481, CB16/12/00241, PI18/00382, PI18/00006, PI18/01219), Generalitat de Catalunya (2017 SGR 507). MINECO through gBFU2015-71371-R grant and the CRIS Cancer Foundation supported work in AP lab. D. Casadevall was supported by ISCIII (Rio Hortega Research Contract CM16/00023 and Juan Rodés Research Contract JR18/00003). F.J. Sánchez-Martín and S. Menéndez were supported by Department de Salut Generalitat de Catalunya (PERIS SLT002/16/00008 and PERIS SLT006/17/00040). M. Qin received financial support from the China Scholarship Council (CSC) for her doctoral fellowship. Work carried out in our laboratories receives support from the European Community through the Regional Development Funding Program (FEDER).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Casadevall D, Hernández-Prat A, García-Alonso S, Arpí-Llucià O, Menéndez S, Qin M, Guardia C, Morancho B, Sánchez-Martín FJ, Zazo S, Gavilán E, Sabbaghi MA, Eroles P, Cejalvo JM, Lluch A, Rojo F, Pandiella A, Rovira A, Albanell J. mTOR inhibition and T-DM1 in HER2-positive breast cancer. Mol Cancer Res. 2022 Jul 6;20(7):1108-21. DOI: 10.1158/1541-7786.MCR-21-0545
  • dc.identifier.doi http://dx.doi.org/10.1158/1541-7786.MCR-21-0545
  • dc.identifier.issn 1541-7786
  • dc.identifier.uri http://hdl.handle.net/10230/54481
  • dc.language.iso eng
  • dc.publisher American Association for Cancer Research (AACR)
  • dc.relation.ispartof Mol Cancer Res. 2022 Jul 6;20(7):1108-21
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2015-71371-R
  • dc.rights © American Association for Cancer Research (AACR) http://dx.doi.org/10.1158/1541-7786.MCR-21-0545
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.subject.keyword Inhibition of mTOR increases the antitumor activity of T-DM1
  • dc.subject.keyword Supporting that the combination of mTOR inhibitors
  • dc.subject.keyword Antibody-drug conjugates warrants clinical evaluation in patients with HER2-positive breast cancer
  • dc.title mTOR inhibition and T-DM1 in HER2-positive breast cancer
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/acceptedVersion