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A fluorogenic probe for predicting treatment response in non-small cell lung cancer with EGFR-activating mutations
Hui Deng1,2,3, Qian Lei4,5,6, Chengdi Wang4
1Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China. huideng0923@hotmail.com.
Abstract:
Therapeutic responses of non-small cell lung cancer (NSCLC) to epidermal growth factor receptor (EGFR) - tyrosine kinase inhibitors (TKIs) are known to be associated with EGFR mutations. However, a proportion of NSCLCs carrying EGFR mutations still progress on EGFR-TKI underlining the imperfect correlation. Structure-function-based approaches have recently been reported to perform better in retrospectively predicting patient outcomes following EGFR-TKI treatment than exon-based method. Here, we develop a multicolor fluorescence-activated cell sorting (FACS) with an EGFR-TKI-based fluorogenic probe (HX103) to profile active-EGFR in tumors. HX103-based FACS shows an overall agreement with gene mutations of 82.6%, sensitivity of 81.8% and specificity of 83.3% for discriminating EGFR-activating mutations from wild-type in surgical specimens from NSCLC patients. We then translate HX103 to the clinical studies for prediction of EGFR-TKI sensitivity. When integrating computed tomography imaging with HX103-based FACS, we find a high correlation between EGFR-TKI therapy response and probe labeling. These studies demonstrate HX103-based FACS provides a high predictive performance for response to EGFR-TKI, suggesting the potential utility of an EGFR-TKI-based probe in precision medicine trials to stratify NSCLC patients for EGFR-TKI treatment.
Insights
A new fluorescence probe (HX103) accurately predicts non-small cell lung cancer (NSCLC) response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). This method aids in personalizing NSCLC treatment strategies for better patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Biotechnology
Background:
- Therapeutic responses in non-small cell lung cancer (NSCLC) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are linked to EGFR mutations.
- A subset of NSCLC patients with EGFR mutations exhibit disease progression despite EGFR-TKI treatment, indicating limitations in current predictive methods.
Purpose of the Study:
- To develop and validate a novel method for profiling active-EGFR in NSCLC tumors.
- To assess the predictive performance of this method for patient response to EGFR-TKI therapy.
Main Methods:
- Development of a multicolor fluorescence-activated cell sorting (FACS) assay utilizing an EGFR-TKI-based fluorogenic probe (HX103).
- Profiling of active-EGFR in NSCLC surgical specimens using HX103-based FACS.
- Integration of HX103-based FACS with computed tomography (CT) imaging in clinical studies to correlate probe labeling with therapy response.
Main Results:
- HX103-based FACS demonstrated high agreement (82.6%) with gene mutations, with 81.8% sensitivity and 83.3% specificity in discriminating EGFR-activating mutations from wild-type.
- A strong correlation was observed between EGFR-TKI therapy response and HX103 probe labeling when integrated with CT imaging.
- The assay effectively predicted patient outcomes following EGFR-TKI treatment.
Conclusions:
- HX103-based FACS offers a robust method for profiling active-EGFR and predicting EGFR-TKI sensitivity in NSCLC patients.
- This EGFR-TKI-based probe shows significant potential for use in precision medicine trials to stratify NSCLC patients for targeted therapy.
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