Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors
Menée à l'aide d'un modèle murin transgénique de cancer du sein HER2+, cette étude met en évidence des mécanismes suggérant l'intérêt d'une stratégie thérapeutique basée sur l'inhibition de CDK4/6 pour surmonter l'apparition d'une résistance à une thérapie ciblée anti HER2
Using transgenic mouse models, cell line-based functional studies, and clinical specimens, we show that cyclin D1/CDK4 mediate resistance to targeted therapy for HER2-positive breast cancer. This is overcome using CDK4/6 inhibitors. Inhibition of CDK4/6 not only suppresses Rb phosphorylation, but also reduces TSC2 phosphorylation and thus partially attenuates mTORC1 activity. This relieves feedback inhibition of upstream EGFR family kinases, resensitizing tumors to EGFR/HER2 blockade. Consequently, dual inhibition of EGFR/HER2 and CDK4/6 invokes a more potent suppression of TSC2 phosphorylation and hence mTORC1/S6K/S6RP activity. The suppression of both Rb and S6RP enhances G1 arrest and a phenotype resembling cellular senescence. In vivo, CDK4/6 inhibitors sensitize patient-derived xenograft tumors to HER2-targeted therapies and delay tumor recurrence in a transgenic model of HER2-positive breast cancer.
Cancer Cell 2016