Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition

This study presents strategies to render triple-negative breast cancers sensitive to CDK4/6 inhibitors. 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...

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Vydáno v:Science advances Ročník 6; číslo 25; s. eabb2210
Hlavní autoři: 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
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States American Association for the Advancement of Science 01.06.2020
Témata:
Cancer
Cell Biology
SciAdv r-articles
ISSN:2375-2548, 2375-2548
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Shrnutí:This study presents strategies to render triple-negative breast cancers sensitive to CDK4/6 inhibitors. 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.
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ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abb2210