Abstract 15624: The Anti-lung Cancer Drug (R)-crizotinib Predisposes and Exacerbates Pulmonary Hypertension
Bibliographic record
Abstract
Introduction: Pulmonary arterial hypertension (PAH) is a vascular disease characterized by persistent elevation of pulmonary vascular resistance leading to right heart failure and death. In 10% of cases, PAH is induced by drugs including chemotherapeutic agents such as RTK inhibitors (e.g. dasatinib). (R)-Crizotinib is an ALK/ROS1/MET inhibitor increasingly used for the treatment of non-small cell lung cancer (NSCLC). Interestingly, (R)-Crizotinib has been shown to induce endothelial cells (EC) dysfunction and is associated with dyspnea and peripheral oedema, 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 administration of (R)-Crizotinib (100mg/kg for 2 weeks) in Sugen/Hypoxia (Su/Hx) PAH rat model significantly increased mortality rates. Compared to vehicle-treated 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 fibrosis and macrophages accumulation in the lungs and right ventricle. In addition, we showed that pretreatment of rats with (R)-Crizotinib exaggerates the response to monocrotaline (MCT, 40mg/kg), as revealed by histological (increase in vascular remodeling) and hemodynamic measurements (mPAP; TPR; CO) (p<0.01; n=7-10). In vitro, (R)-Crizotinib reduced MET and AKT activation (WB) in human PA endothelial cells promoting endothelial dysfunction via decreased proliferation (Ki67) and increased apoptosis (Annexin V) rates. In addition, (R)-Crizotinib interferes with autophagy flux (increase in LC3-II and p62 accumulation) and was accompanied by the appearance of atypical morphological phenotypes in PA endothelial cells (multinucleated cells). Conclusion: We showed for the first time that (R)-Crizotinib treatment predisposes and exacerbates PAH in animal models (Sugen/Hypoxia and monocrotaline). Understanding the mechanism will provide promising perspectives for a better management of patients treated with (R)-Crizotinib or ALK/ROS1/MET inhibitors.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".