代表初治、化疗和靶向治疗耐药患者群体的一组EGFR突变肺癌XPDX模型的建立与表征

Background : Epidermal growth factor receptor (EGFR) mutations represent clinically actionable driver alterations in non-small cell lung cancer (NSCLC), defining a molecular subset with distinct biology, therapeutic vulnerabilities, and patterns of resistance. While common activating mutations including exon 19 deletions (19del) and L858R substitutions have well-characterized responses EGFR tyrosine kinase inhibitors (TKIs), the landscape of EGFR-driven disease is increasingly complex. Uncommon EGFR variants (e.g., D761Y, Y801C, G863C) and acquired compound mutations such as T790M and C797S as well as other resistance mechanisms drive resistance and disease progression. These biologically diverse contexts underscore the need for translational research platforms that accurately represent clinical heterogeneity and enable evaluation of therapeutic strategies across the evolving spectrum of EGFR-mutant disease. To this end, we have established and characterized a panel of EGFR-mutant lung PDX models representing naïve, chemotherapy, and targeted therapy-resistant patient populations. These models were characterized for receptor expression, genomic alterations, and in vivo drug sensitivity to relevant therapies. Methods : XPDX models representing EGFR 19del and L858R-mutated lung cancer were established from primary or metastatic samples collected from naïve or pretreated patients; additional lung XPDX models harboring uncommon EGFR mutations were also established. Resulting models were passaged and further developed until growth stabilization. Resulting models were characterized using histopathology, WES and RNA seq and in vivo drug sensitivity studies. For in vivo studies, single agent osimertinib or afatinib were evaluated at standard treatment regimens. Study endpoints included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion. Results : Histopathology confirmed models as similar to patient in most cases. Sequencing identified EGFR co-mutations including T790M, C797S, and several uncommon mutations including D761Y (ST5185B), Y801C (ST6984), G863C (STM225C), and an A767ASVG inframe insertion (ST6963). Several EGFR 19del and L858R-mutated models from naïve patients were sensitive to osimertinib or afatinib while most models from patients treated with one or more EGFR inhibitors were resistant to single agent therapies. ST5185B, ST6963, and STM225C were insensitive to either therapy; however, afatinib but not osimertinib was active towards ST6984. Conclusion : We have established and characterized a panel of EGFR-mutated lung XPDX models representing naïve, chemotherapy, and targeted therapy-resistant patients. These models can be utilized as a valuable tool in better understanding EGFR-mutated lung cancer.