Cyclin dependent kinase 4 and 6 inhibitors (CDK4/6i) induce lysosomal changes in breast cancer cells. Resistant cells display increased levels of Transcription Factor EB, a master regulator of genes associated with lysosomes, along with proteolytic cathepsins (CTSD) and lysosomal membrane protein CD68 (LAMP4). Prolonged exposure to CDK4/6i also leads to elevated levels of antiapoptotic protein B cell lymphoma 2 (BCL2). Resistant cells leverage these changes to sustain survival and increase metastatic potential but are susceptible to lysosome destabilizers, which restore sensitivity to CDK4/6i and reduce metastatic potential.

The flowchart of the study