Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers With CDK4/6 Inhibitors

Resistance to anti-HER2 therapy leads to relapse and progression of HER2-positive breast cancers. Here, we show that tumor cells that resist HER2 pathway blockade retain expression of cyclin D1, and in a new transgenic mouse model ultimately give rise to cyclin D1/CDK4-dependent recurrences. Furthermore, the cyclin D1/CDK4 axis functionally mediates de novo and acquired resistance to anti-HER2 therapies, and a CDK4/6 inhibitor overcomes this. When combined, HER2 and CDK4/6 inhibitors synergistically reduce tumor cell viability by enhancing cell cycle arrest at the G1/S checkpoint, in association with reduced phosphorylation of both RB and S6RP. In vivo, CDK4/6 inhibition improves the efficacy of HER2 targeted therapy in both sensitive and resistant xenografts, and importantly also delays spontaneous tumor recurrence.