Mechanism of Action of Palbociclib
Palbociclib is a selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) that blocks cell cycle progression by preventing phosphorylation of the retinoblastoma (Rb) protein, thereby arresting cells in the G1 phase and inhibiting their transition to S phase. 1
Molecular Mechanism
Palbociclib inhibits the CDK4/6-cyclin D complex, which is downstream of signaling pathways that lead to cellular proliferation 1
The drug blocks Rb protein phosphorylation, resulting in reduced E2F transcription factor expression and signaling, which increases growth arrest 1
By preventing Rb phosphorylation, palbociclib stops cells from passing through the G1-restriction point, thereby preventing commitment to cell division 2
Palbociclib binds in the ATP-binding cleft between the small and large lobes of CDK4/6, forming hydrogen bonds with residues in the hinge segment similar to ATP binding 2
Cellular Effects
In estrogen receptor (ER)-positive breast cancer cell lines, palbociclib reduces cellular proliferation by blocking progression from G1 into S phase of the cell cycle 1
When combined with antiestrogens, palbociclib leads to increased cell senescence compared to each drug alone, which is sustained for up to 6 days following palbociclib removal and is greater if antiestrogen treatment is continued 1
The expression of retinoblastoma protein (Rb) is required for palbociclib to demonstrate its antitumor effect, as shown in preclinical studies 3
Synergistic Activity with Endocrine Therapy
Combination treatment with palbociclib and antiestrogens produces enhanced growth arrest compared to treatment with each drug alone in ER-positive breast cancer cell lines 1
In vivo studies using patient-derived ER-positive breast cancer xenograft models demonstrated that palbociclib combined with letrozole increased inhibition of Rb phosphorylation, downstream signaling, and tumor growth compared to each drug alone 1
Preclinical studies confirmed that most cell lines sensitive to palbociclib are ER-positive, supporting its use in hormone receptor-positive breast cancer 3
Selectivity and Specificity
Palbociclib targets CDK4/6 with IC50 values in the low nanomolar range, demonstrating high selectivity for these kinases 2
The drug interacts with catalytic spine residues CS6 and CS7, similar to ATP, which explains its potent inhibitory activity 2
Human bone marrow mononuclear cells treated with palbociclib do not become senescent and resume proliferation following drug withdrawal, suggesting selectivity for cancer cells over normal proliferating cells 1