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Published on: November 22, 2021
Resistance gene expression determines the in vitro chemosensitivity of non-small cell lung cancer (NSCLC)
Sharon Glaysher1, Dennis Yiannakis, Francis G Gabriel
1Translational Oncology Research Centre, Queen Alexandra Hospital, Portsmouth PO6 3LY, UK. sharonglaysher@googlemail.com
Background:
NSCLC exhibits considerable heterogeneity in its sensitivity to chemotherapy and similar heterogeneity is noted in vitro in a variety of model systems. This study has tested the hypothesis that the molecular basis of the observed in vitro chemosensitivity of NSCLC lies within the known resistance mechanisms inherent to these patients' tumors.
Methods:
The chemosensitivity of a series of 49 NSCLC tumors was assessed using the ATP-based tumor chemosensitivity assay (ATP-TCA) and compared with quantitative expression of resistance genes measured by RT-PCR in a Taqman Array following extraction of RNA from formalin-fixed paraffin-embedded (FFPE) tissue.
Results:
There was considerable heterogeneity between tumors within the ATP-TCA, and while this showed no direct correlation with individual gene expression, there was strong correlation of multi-gene signatures for many of the single agents and combinations tested. For instance, docetaxel activity showed some dependence on the expression of drug pumps, while cisplatin activity showed some dependence on DNA repair enzyme expression. Activity of both drugs was influenced more strongly still by the expression of anti- and pro-apoptotic genes by the tumor for both docetaxel and cisplatin. The doublet combinations of cisplatin with gemcitabine and cisplatin with docetaxel showed gene expression signatures incorporating resistance mechanisms for both agents.
Conclusion:
Genes predicted to be involved in known mechanisms drug sensitivity and resistance correlate well with in vitro chemosensitivity and may allow the definition of predictive signatures to guide individualized chemotherapy in lung cancer.
Insights
Molecular signatures in non-small cell lung cancer (NSCLC) predict chemotherapy response. Gene expression patterns correlate with in vitro chemosensitivity, paving the way for personalized lung cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacogenomics
Background:
- Non-small cell lung cancer (NSCLC) displays significant variability in chemotherapy response.
- This heterogeneity is mirrored in in vitro models, suggesting underlying molecular mechanisms.
- This study investigated if known drug resistance mechanisms explain NSCLC chemosensitivity in vitro.
Purpose of the Study:
- To test the hypothesis that inherent tumor resistance mechanisms dictate NSCLC chemosensitivity.
- To correlate in vitro chemosensitivity data with quantitative gene expression of resistance markers.
- To explore the potential for developing predictive gene signatures for individualized lung cancer chemotherapy.
Main Methods:
- Assessed chemosensitivity of 49 NSCLC tumors using the ATP-based tumor chemosensitivity assay (ATP-TCA).
- Quantified expression of resistance genes via RT-PCR in a Taqman Array using RNA from FFPE tissues.
- Compared ATP-TCA results with gene expression data to identify correlations.
Main Results:
- Observed significant heterogeneity in tumor chemosensitivity.
- Found strong correlations between multi-gene signatures and the activity of single agents and combinations, rather than individual gene expression.
- Docetaxel activity linked to drug pump expression; cisplatin activity to DNA repair enzyme expression.
- Apoptotic gene expression strongly influenced the activity of both docetaxel and cisplatin.
- Combination therapies showed gene expression signatures reflecting resistance mechanisms of both agents.
Conclusions:
- Genes involved in drug sensitivity and resistance mechanisms correlate with in vitro chemosensitivity.
- Identified potential for predictive gene signatures to guide personalized chemotherapy in NSCLC.
- Molecular profiling may enhance individualized treatment strategies for lung cancer patients.
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