The combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy has revolutionized treatment for hormone receptor-positive (HR+) metastatic breast cancer. However, the emergence of resistance in most patients often leads to treatment discontinuation with no consensus on effective second-line therapies. The therapeutic benefits of maintaining CDK4/6i or incorporating CDK2 inhibitors (CDK2i) after disease progression remain unclear. Here, we demonstrate that sustained CDK4/6i therapy, either alone or combined with CDK2i, significantly suppresses the growth of drug-resistant HR+ breast cancer. Continued CDK4/6i treatment induces a non-canonical pathway for retinoblastoma protein (Rb) inactivation via post-translational degradation, resulting in diminished E2F activity and delayed G1 progression. Importantly, our data highlight that CDK2i should be combined with CDK4/6i to effectively suppress CDK2 activity and overcome resistance. We also identify cyclin E overexpression as a key driver of resistance to CDK4/6 and CDK2 inhibition. These findings provide crucial insights into overcoming resistance in HR+ breast cancer, supporting the continued use of CDK4/6i and the strategic incorporation of CDK2i to improve therapeutic outcomes.