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Pharmacological CDK4/6 inhibition promotes vulnerability to lysosomotropic agents in breast cancer

ABSTRACT: Breast cancer is a leading cause of mortality worldwide. Pharmacological inhibitors of Cyclin-Dependent Kinases (CDK) 4 and 6 (CDK4/6i) inhibit breast cancer growth by inducing a senescent-like state. However, long-term treatment efficacy remains hindered by the development of drug resistance. Clearance of senescent-like cancer cells may extend the durability of treatment. In this study, we showed that CDK4/6i-treated breast cancer cells exhibit various senescence-associated phenotypes, but remain insensitive to common senolytic compounds. By searching for novel vulnerabilities, we identified a significantly increased lysosomal mass and altered lysosomal structure across various breast cancer cell types upon exposure to CDK4/6i in preclinical systems and clinical specimens. We demonstrated that these lysosomal alterations render breast cancer cells sensitive to lysosomotropic agents, such as L-leucyl-L-leucine methyl ester (LLOMe) and salinomycin. Importantly, sequential treatment with CDK4/6i/lysosomotropic agents effectively reduced the growth of both Hormone Receptor-positive (HR+) and triple-negative breast cancer (TNBC) cells in vivo. This sequential therapeutic strategy offers a promising approach to eliminate CDK4/6i-induced senescent(-like) cells, potentially reducing tumor recurrence and enhancing the overall efficacy of breast cancer therapy.

SUBMITTER: Jamil Nehme

PROVIDER: S-SCDT-10_1038-S44318-025-00371-X | biostudies-other |

REPOSITORIES: biostudies-other

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