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Updated: Jul 12, 2026
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
Small Cell Lung Cancer: Screening of Kinase Inhibitors
Hamilton Gerhard1, Marie-Therese Eggerstorfer2, Sandra Stickler2
1Institute of Pharmacology, Medical University of Vienna, Vienna, Austria. gerhard.hamilton@meduniwien.ac.at.
Abstract:
Small cell lung cancer (SCLC) exhibits extreme numbers of circulating tumor cells (CTCs) that are operative in tumor dissemination and possibly drug resistance, ultimately resulting in a dismal prognosis. Tumor cells depend on kinases, which are triggered by a range of growth factors for their malignant proliferation. Insulin-like growth factor-I receptor (IGF-1) and vascular endothelial growth factor receptor (VEGFR), c-Kit, epidermal growth factor receptor (EGFR), as well as downstream signaling transmitters such as phosphoinositide 3-kinase (PI3K), Akt and the mammalian target of rapamycin (mTOR) and a range of other kinases were investigated as potential anti-tumor targets in SCLC. Despite the expression of rational targets, the studies with tyrosine kinase inhibitors (TKIs) in SCLC have been very disappointing in the clinic. The preclinical activity of kinase inhibitors against native and resistant SCLC cell lines failed to predict efficacy in patients. Screening of a kinase inhibitor library showed activity of most compounds against single SCLC CTC cells but high chemoresistance of BHGc10 spheroids (termed tumorospheres). Only a few hydrophobic multitarget inhibitors proved active against the spheroids, and drugs that failed in clinical trials targeting IGF-1R, AURORA kinase and Polo kinases showed low activity against CTC tumorospheres. These results demonstrate that for SCLC, kinase inhibitors should be tested against spheroids to obtain a better prediction of their potential clinical activity.
Insights
Small cell lung cancer (SCLC) circulating tumor cells (CTCs) show resistance to kinase inhibitors. Testing inhibitors against tumorospheres, not single cells, may better predict clinical efficacy in SCLC patients.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Small cell lung cancer (SCLC) is characterized by numerous circulating tumor cells (CTCs) contributing to metastasis and drug resistance.
- Kinases, activated by growth factors, are crucial for SCLC proliferation, making them potential therapeutic targets.
- Despite targeting kinases like IGF-1R and VEGFR, clinical trials with tyrosine kinase inhibitors (TKIs) in SCLC have yielded disappointing results.
Purpose of the Study:
- To investigate the efficacy of kinase inhibitors against SCLC circulating tumor cells (CTCs).
- To evaluate whether testing kinase inhibitors against SCLC tumorospheres predicts clinical activity better than testing against single CTCs.
Main Methods:
- Screening of a kinase inhibitor library against single SCLC CTCs and SCLC tumorospheres (BHGc10 spheroids).
- Assessing the activity of various kinase inhibitors, including those previously tested in clinical trials.
Main Results:
- Most kinase inhibitors showed activity against single SCLC CTCs.
- SCLC tumorospheres exhibited high chemoresistance to most tested kinase inhibitors.
- Only a few hydrophobic multitarget inhibitors were effective against tumorospheres.
- Drugs that failed in clinical trials targeting IGF-1R, AURORA kinase, and Polo kinases showed low activity against CTC tumorospheres.
Conclusions:
- Preclinical efficacy of kinase inhibitors against single SCLC cells does not accurately predict clinical outcomes.
- Testing kinase inhibitors against SCLC tumorospheres is a more reliable method for predicting potential clinical activity.
- This approach may improve the selection of effective kinase inhibitors for SCLC treatment.
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