Introduction: Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by persistent elevation of pulmonary vascular resistance. The disease leads spontaneously to right heart failure and death. In 10% of cases, PAH is induced by drugs. Recently, PAH induced by chemotherapeutic agents such as RTK inhibitors (e.g. dasatinib) has been described. (R)-Crizotinib is a ALK/ROS1/MET inhibitor increasingly used for the treatment of some non-small cell lung cancer. Interestingly, (R)-Crizotinib has been shown to induce endothelial cells (EC) dysfunction and is symptomatically associated with dyspnea and peripheral oedema in some patients, which are central symptoms of PAH. We thus hypothesized that chronic administration of (R)-Crizotinib exacerbates and predisposes PAH.
Material and results: We found that daily oral administration of (R)-Crizotinib (100mg/kg for 2 weeks) in Sugen/Hypoxia (Su/Hx)-challenged rats with established PAH significantly increased mortality rate. Compared to vehicle-treated (Su/Hx) rats, (R)-Crizotinib was associated with worsening of hemodynamic parameters (RVSP, mPAP, Sv, CO and TPR measured by right heart catheterization; p<0.05; n=4-6). Histologically, (R)-Crizotinib enhanced pulmonary arteries (PA) wall thickness (EVG stain; p<0.05) and increased accumulation of macrophage and fibrosis within the lungs and RV. In addition, we observed that pretreatment of rats with (R)-Crizotinib exaggerates the response to monocrotaline (MCT, 40mg/kg) administration, as revealed by histological (increase in vascular remodeling) and hemodynamic measurements (mean PAP; TPR; CO) (p<0.01; n=7-10). In vitro, (R)-Crizotininb reduced MET and AKT activation (WB) in human PA endothelial cells promoting endothelial dysfunction, (decreased proliferation (Ki67) and increased apoptosis (Annexin V).
Conclusion: We documented for the first time that (R)-Crizotinib treatment predisposes and excacerbates PAH in animal models. This study could have major clinical relevance in the management of patients treated with (R)-Crizotinib or next generation ALK/ROS1/MET inhibitors.