Journal
MOLECULAR CANCER RESEARCH
Volume 20, Issue 7, Pages 1108-1121Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-21-0545
Keywords
-
Categories
Funding
- ISCIII (CIBERONC) [CB16/12/00481, CB16/12/00241, PI18/00382, PI18/00006, PI18/01219]
- Generalitat de Catalunya [2017 SGR 507]
- MINECO [gBFU2015-71371-R]
- CRIS Cancer Foundation
- ISCIII [CM16/00023]
- Juan Rode's Research [JR18/00003]
- Department de Salut Generalitat de Catalunya [PERIS SLT002/16/00008, PERIS SLT006/17/00040]
- China Scholarship Council (CSC)
- European Community
Ask authors/readers for more resources
The combination of everolimus and T-DM1 showed strong antitumor effects in HER2-positive breast cancer, potentially due to mTOR-dependent lysosomal processing of T-DM1.
? 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available