Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition
Author(s)
Fassl, Anne; Brain, Christopher; Abu-Remaileh, Monther; Stukan, Iga; Butter, Deborah; Stepien, Piotr; Feit, Avery S.; Bergholz, Johann; Michowski, Wojciech; Otto, Tobias; Sheng, Qing; Loo, Alice; Michael, Walter; Tiedt, Ralph; DeAngelis, Carmine; Schiff, Rachel; Jiang, Baishan; Jovanovic, Bojana; Nowak, Karolina; Ericsson, Maria; Cameron, Michael; Gray, Nathanael; Dillon, Deborah; Zhao, Jean J.; Sabatini, David M.; Jeselsohn, Rinath; Brown, Myles; Polyak, Kornelia; Sicinski, Piotr; ... Show more Show less
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© 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.
Date issued
2020-06Journal
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
ISSN
2375-2548