Mechanisms of cell cycle regulation by CDK4 / 6 and pathways for the formation of resistance to their inhibitors (literature review)

Cyclin-dependent kinase 4 / 6 inhibitors (CDK4 / 6i) have become a standard component of therapy for hormone receptor — positive (HR+) / HER2‑negative (HER2–) breast cancer (BC). However, in most patients, their clinical benefit is only temporary. Acquired resistance is not the exception but the rule, representing a major barrier to achieving durable disease control. To summarize current knowledge on resistance mechanisms, we conducted a literature search and analysis in the PubMed / MEDLINE, Scopus, and Web of Science databases covering the period 2015–2024, supplemented by seminal publications from earlier years.

This review summarizes current evidence on the molecular mechanisms underlying resistance to CDK4 / 6 inhibitors. It highlights alterations in cell-cycle regulation and activation of compensatory intracellular signaling cascades that enable tumor cells to circumvent the effects of these agents.

The principal mechanisms of resistance to CDK4 / 6i include altered expression of the kinases themselves (CDK6 overexpression or CDK4 downregulation), loss or reduced expression of the estrogen receptor (ER), dysfunction of the retinoblastoma protein (Rb), and loss of the APC / C co-activator FZR1, leading to APC / C^MR1 complex dysfunction and CDK hyperactivation. Of particular interest is amplification of the CDKN2A tumor-suppressor gene, which alters the functional properties of its product, p16^INK4a, endowing it with noncanonical oncogenic activity. Alternative signaling pathways also play key roles in resistance development, including hyperactivation of PI3K — AKT — mTOR, activation of FGFR, and dysregulation of the Hippo kinase pathway. PI3K — AKT — mTOR hyperactivation, often associated with loss of the tumor suppressor PTEN, correlates not only with resistance to CDK4 / 6i but also with reduced sensitivity to PI3K inhibitors. FGFR activation stimulates MAPK and PI3K signaling cascades and promotes ligand-independent ER activation through protein phosphorylation. Dysregulation of the Hippo pathway drives nuclear translocation of YAP / TAZ and enhances expression of proliferation-related genes, including CDK6. The diversity of these resistance mechanisms turns therapy into a “whack-a-mole” scenario: inhibition of one pathway inevitably triggers activation of another. Overcoming resistance therefore requires the development of rational combination strategies that synergistically target both the canonical proliferation pathway and critical compensatory cascades. Such an approach holds promise for the development of truly personalized therapies for patients with HR+ / (HER2–) breast cancer.

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