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Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition
Name
eabb2210.full.pdf
Description
Published version
Size
1.2 MB
Format
Adobe PDF
Checksum (MD5)
e4e4d1f1d9a6270c8e47d8c860d780f7
Author(s)
Fassl, Anne
Brain, Christopher
Abu-Remaileh, Monther
Stukan, Iga
Butter, Deborah
Stepien, Piotr
Feit, Avery S
Bergholz, Johann
Michowski, Wojciech
Otto, Tobias
Date Issued
2020
Journal
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Version
Final published version
Abstract
© 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). Inhibitors of cyclin-dependent kinases CDK4 and CDK6 have been approved for treatment of hormone receptor-positive breast cancers. In contrast, triple-negative breast cancers (TNBCs) are resistant to CDK4/6 inhibition. Here, we demonstrate that a subset of TNBC critically requires CDK4/6 for proliferation, and yet, these TNBC are resistant to CDK4/6 inhibition due to sequestration of CDK4/6 inhibitors into tumor cell lysosomes. This sequestration is caused by enhanced lysosomal biogenesis and increased lysosomal numbers in TNBC cells. We developed new CDK4/6 inhibitor compounds that evade the lysosomal sequestration and are efficacious against resistant TNBC. We also show that coadministration of lysosomotropic or lysosome-destabilizing compounds (an antibiotic azithromycin, an antidepressant siramesine, an antimalaria compound chloroquine) renders resistant tumor cells sensitive to currently used CDK4/6 inhibitors. Lastly, coinhibition of CDK2 arrested proliferation of CDK4/6 inhibitor-resistant cells. These observations may extend the use of CDK4/6 inhibitors to TNBCs that are refractory to current anti-CDK4/6 therapies.
Terms of Use
Creative Commons Attribution NonCommercial License 4.0
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DOI of Published Version
10.1126/SCIADV.ABB2210
