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

Casadevall Aguilar, David; Hernández Prat, Anna, 1984-; García-Alonso, Sara; Arpí Llucià, Oriol; Menéndez, Silvia; Qin, Mengjuan; Guardia Valenzuela, Cristina, 1990-; Morancho Armisen, Beatriz; Sánchez-Martín, Francisco Javier; Zazo, Sandra; Gavilán, Elena; Sabbaghi Mehrjardi, Mohammad Ali; Eroles, Pilar; Cejalvo, Juan M.; Lluch, Ana; Rojo, Federico; Pandiella, Atanasio; Rovira, Ana; Albanell Mestres, Joan

doi:http://dx.doi.org/10.1158/1541-7786.MCR-21-0545

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

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

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.