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

Abstract

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.

• Authors: Anne Fassl, Christopher Brain, Monther Abu-Remaileh, Iga Stukan, Deborah Butter, Piotr Stepien, Avery S Feit, Johann Bergholz, Wojciech Michowski, Tobias Otto, Qing Sheng, Alice Loo, Walter Michael, Ralph Tiedt, Carmine DeAngelis, Rachel Schiff, Baishan Jiang, Bojana Jovanovic, Karolina Nowak, Maria Ericsson, Michael Cameron, Nathanael Gray, Deborah Dillon, Jean J Zhao, David M Sabatini, Rinath Jeselsohn, Myles Brown, Kornelia Polyak, Piotr Sicinski
• Journal: Science advances (Sci Adv) Vol. 6 Issue 25 Pg. eabb2210 (06 2020) ISSN: 2375-2548 [Electronic] United States
• PMID: 32704543 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 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).