The Cdk4/6 Inhibitor, Palbociclib Intensifies Pulmonary Inflammation In Bleomycin-Induced Lung Fibrosis

Rationale: Inhibitors of cyclin-dependent kinases 4/6 (CDK4/6) are commonly used for treatment of several forms of cancer. During normal cell proliferation, CDK4/6 binds cyclin D1, which then inactivates the retinoblastoma protein and consequently activation of genes important for cell cycle progression. Palbociclib and other CDK4/6 inhibitors block this process. Due to this anti-proliferative mode of action, we speculate that palbociclib could attenuate the development of bleomycin-induced lung fibrosis. Methods: In a pre-clinical setting, mice were treated with bleomycin (i.t.) and then co-treated with or without palbociclib (150 mg/kg/day). After 14 days, lung function, collagen deposition and pulmonary inflammation were analysed. Results: Bleomycin treatment led to an increase of lung fibrosis and inflammation with a concomitant decrease in lung function. Palbociclib treatment significantly decreased the collagen deposition in the lung of bleomycin-treated mice, but did not improve lung function. Importantly, palbociclib augmented the levels of inflammatory cells (including macrophages and T cells) in the bronchoalveolar lavage. Conclusions: This study supports the recent alert from the Food and Drug Administration (FDA) that use of CDK4/6 inhibitors, such as palbociclib, may lead to severe pulmonary inflammation. Our observations of heightened pulmonary inflammation in the bleomycin model following palbociclib treatment, emphasizes the risk of severe inflammatory adverse effects in the lung, especially in patients with known pulmonary risk factors and highlights the necessity to carefully monitor all patients treated with CDK4/6 inhibitors for signs of lung inflammation.