The Brain-Penetrant Pan-ErbB Inhibitor Poziotinib Effectively Targets HER2+ Breast Cancer Brain Metastases
Bibliographic record
Abstract
Brain metastasis occurs in about 50% of all women with metastatic HER2+ breast cancer and confers poor prognosis for patients. Despite effective HER2-targeted treatments of peripheral HER2+ breast cancer with trastuzumab and HER2 inhibitors, limited brain permeability renders these treatments inefficient for HER2+ breast cancer brain metastasis. The scarcity of suitable patient-derived in vivo models for HER2+ breast cancer brain metastasis has curtailed the study of molecular mechanisms that promote growth and therapeutic resistance in brain metastasis. In this study, we generated and characterized a luminal B HER2+ breast cancer brain metastasis cell model (BCBM94) isolated from a patient with HER2+ brain metastasis. Repeated hematogenic xenografting of BCBM94 consistently generated breast cancer brain metastasis in mice. The clinical receptor tyrosine kinase inhibitor (RTKi) lapatinib blocked phosphorylation of all ERBB receptors (ERBB1-4) and induced the intrinsic apoptosis pathway in BCBM94. Neuregulin 1 (Nrg1), an ERBB3/ERBB4 ligand that is abundantly expressed in the brain, abrogated lapatinib-induced apoptosis in HER2+ BCBM94 and BT474 models. ErbB3 signaling pathways that involved PI3K-AKT and the phosphorylation of BAD at serine 136 to prevent apoptosis were essential for Nrg1-induced survival. High-throughput RTKi screening identified the brain-penetrant pan-ErbB inhibitor poziotinib as a highly potent compound that reduced cell viability in HER2+ breast cancer brain metastasis in the presence of NRG1. Two weeks of poziotinib treatment successfully ablated BCBM94 and BT474 HER2+ brain tumors in vivo. In conclusion, this study established a patient-derived HER2+ breast cancer brain metastasis model and identified poziotinib as a highly efficacious RTKi with excellent brain penetrability that eliminated HER2+ breast cancer brain metastasis. Significance: Development of a preclinical patient-derived model to study HER2+ breast cancer brain metastasis enabled the identification of the irreversible pan-ERBB inhibitor poziotinib as highly efficacious in treating brain metastatic tumors.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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 | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".