mTOR Inhibition and T-DM1 in HER2-Positive Breast Cancer.

Fecha de publicación: 06/07/2022

Autores de INCLIVA

Participantes ajenos a INCLIVA

Casadevall, David
Hernandez-Prat, Anna
Garc A-Alonso, Sara
Arpi-Llucia, Oriol
Menendez, Silvia
Qin, Mengjuan
Guardia, Cristina
Morancho, Beatriz
Sanchez-Mart N, Francisco Javier
Zazo, Sandra
Gavilan, Elena
Sabbaghi, MohammadA
Rojo, Federico
Pandiella, Atanasio
Rovira, Ana
Albanell, Joan

Grupos y Plataformas de I+D+i

Grupo de Investigación en Biología en Cáncer de mama

Leading Researcher

Pilar Eroles Asensio

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. IMPLICATIONS: Inhibition of mTOR increases the antitumor 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.