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Bromodomain and hedgehog pathway targets in small cell lung cancer
Gurmeet Kaur1, Russell A Reinhart2, Anne Monks2
1Molecular Pharmacology Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.
Abstract:
Small cell lung cancer (SCLC) is an extremely aggressive cancer that frequently recurs. Twenty-three human SCLC lines were selected representing varied Myc status. Gene expression of lung cancer, stem-like, hedgehog pathway, and notch pathway genes were determined by RT(2)-PCR array and Exon 1.0 ST array. Etoposide and topotecan concentration response was examined. The IC50's for etoposide and topotecan ranged over nearly 3 logs upon 96 hrs exposure to the drugs. Myc status, TOP2A, TOP2B and TOP1 mRNA expression or topoisomerase 1 and topoisomerase 2 protein did not account for the range in the sensitivity to the drugs. γ-secretase inhibitors, RO429097 and PF-03084014, had little activity in the SCLC lines over ranges covering the clinical Cmax concentrations. MYC amplified lines tended to be more sensitive to the bromodomain inhibitor JQ1. The Smo antagonists, erismodegib and vismodegib and the Gli antagonists, HPI1 and SEN-450 had a trend toward greater sensitivity of the MYC amplified line. Recurrent SCLC is among the most recalcitrant cancers and drug development efforts in this cancer are a high priority.
Insights
This study investigated drug sensitivity in small cell lung cancer (SCLC) cell lines. MYC amplified SCLC lines showed increased sensitivity to specific targeted therapies, offering potential new avenues for treating this aggressive cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Small cell lung cancer (SCLC) is a highly aggressive malignancy with a propensity for recurrence.
- Developing effective treatments for recurrent SCLC remains a critical challenge in oncology.
Purpose of the Study:
- To evaluate the drug sensitivity of various human SCLC cell lines with differing Myc status.
- To explore potential therapeutic targets including stem-like, hedgehog, and notch pathways in SCLC.
Main Methods:
- Utilized 23 human SCLC cell lines with diverse Myc gene amplification status.
- Performed gene expression analysis using RT(2)-PCR and Exon 1.0 ST arrays.
- Assessed drug responses to etoposide, topotecan, gamma-secretase inhibitors, bromodomain inhibitors, and hedgehog pathway antagonists.
Main Results:
- Significant variability in etoposide and topotecan IC50 values was observed across SCLC lines.
- Myc status, TOP2A/B, and TOP1 expression did not fully explain drug sensitivity.
- Gamma-secretase inhibitors showed limited activity; MYC amplified lines were more sensitive to JQ1 and showed a trend towards sensitivity to Smo/Gli antagonists.
Conclusions:
- Myc amplification may influence SCLC sensitivity to targeted therapies like JQ1 and hedgehog pathway inhibitors.
- Further investigation into MYC-targeted therapies is warranted for recurrent SCLC.
- Identifying predictive biomarkers for SCLC treatment response is a high priority.
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