A fluorogenic probe for predicting treatment response in non-small cell lung cancer with EGFR-activating mutations

• Published in: Nature communications 2022-11, Vol.13 (1), p.6944-19, Article 6944
• Main Authors: Deng, Hui, Lei, Qian, Wang, Chengdi, Wang, Zhoufeng, Chen, Hai, Wang, Gang, Yang, Na, Huang, Dan, Yu, Quanwei, Yao, Mengling, Xiao, Xue, Zhu, Guonian, Cheng, Cheng, Li, Yangqian, Li, Feng, Tian, Panwen, Li, Weimin
• Format: Article
• Language: English
• Subjects: 14/1; 14/19; 38/23; 38/90; 45/77; 631/92/96; 692/699/67/1612/1350; 82/1; 82/51; 96; 96/31; Carcinoma, Non-Small-Cell Lung - diagnostic imaging; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Clinical trials; Computed tomography; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - genetics; Flow cytometry; Fluorescence; Growth factors; Humanities and Social Sciences; Humans; Inhibitors; Kinases; Lung cancer; Lung Neoplasms - diagnostic imaging; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; multidisciplinary; Mutation; Non-small cell lung carcinoma; Patients; Performance prediction; Precision medicine; Protein Kinase Inhibitors - adverse effects; Protein-tyrosine kinase; Receptors; Retrospective Studies; Science; Science (multidisciplinary); Sensitivity; Small cell lung carcinoma; Structure-function relationships; Tumors; Tyrosine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-34627-5

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. The presence of activating epidermal growth factor receptor (EGFR) mutations in patients with lung cancer correlates to improved response to EGFR-tyrosine kinase inhibitors. Here, the authors present a fluorescence-activated cell sorting assay to identify EGFR mutations with functional activity in patients and demonstrate its utility in predicting response to EGFR-TKI.