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Updated: Jun 18, 2026
A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
Integrative study of lung cancer adeno-to-squamous transition in EGFR TKI resistance identifies RAPGEF3 as a
Hua Wang1,2, Shijie Tang1, Qibiao Wu1,2
1Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
Abstract:
Although adeno-to-squamous transition (AST) has been observed in association with resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in clinic, its causality, molecular mechanism and overcoming strategies remain largely unclear. We here demonstrate that squamous transition occurs concomitantly with TKI resistance in PC9-derived xenograft tumors. Perturbation of squamous transition via DNp63 overexpression or knockdown leads to significant changes in TKI responses, indicative of a direct causal link between squamous transition and TKI resistance. Integrative RNA-seq, ATAC-seq analyses and functional studies reveal that FOXA1 plays an important role in maintaining adenomatous lineage and contributes to TKI sensitivity. FOXM1 overexpression together with FOXA1 knockout fully recapitulates squamous transition and TKI resistance in both PC9 xenografts and patient-derived xenograft (PDX) models. Importantly, pharmacological inhibition of RAPGEF3 combined with EGFR TKI efficiently overcomes TKI resistance, especially in RAPGEF3high PDXs. Our findings provide novel mechanistic insights into squamous transition and therapeutic strategy to overcome EGFR TKI resistance in lung cancer.
Insights
Squamous transition causes resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in lung cancer. Inhibiting RAPGEF3 with EGFR TKI overcomes this resistance, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Adeno-to-squamous transition (AST) is linked to resistance against epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in lung cancer.
- The precise causality, molecular underpinnings, and effective strategies to overcome AST-mediated TKI resistance remain poorly understood.
Purpose of the Study:
- To elucidate the causal relationship between AST and TKI resistance.
- To identify the molecular mechanisms driving AST and TKI resistance.
- To develop novel therapeutic strategies to overcome AST-induced TKI resistance in lung cancer.
Main Methods:
- Utilized PC9-derived xenograft models and patient-derived xenograft (PDX) models.
- Performed perturbation studies involving DNp63 overexpression/knockdown.
- Conducted integrative RNA-sequencing (RNA-seq) and ATAC-sequencing (ATAC-seq) analyses.
- Investigated the roles of FOXA1 and FOXM1 in lineage maintenance and TKI response.
- Evaluated the efficacy of combined pharmacological inhibition of RAPGEF3 and EGFR TKI.
Main Results:
- Squamous transition was observed concurrently with TKI resistance in xenograft models.
- Modulating DNp63 levels significantly altered TKI responses, confirming a causal link between AST and TKI resistance.
- FOXA1 was identified as crucial for maintaining adenomatous lineage and TKI sensitivity.
- FOXM1 overexpression and FOXA1 knockout successfully replicated AST and TKI resistance in both PC9 and PDX models.
- Combined inhibition of RAPGEF3 and EGFR TKI demonstrated significant efficacy in overcoming TKI resistance, particularly in RAPGEF3-high PDXs.
Conclusions:
- Squamous transition is a direct driver of EGFR TKI resistance in lung cancer.
- FOXA1 and FOXM1 play critical roles in the molecular mechanisms underlying AST and TKI resistance.
- Pharmacological inhibition of RAPGEF3 in combination with EGFR TKI presents a promising therapeutic approach to overcome TKI resistance in a subset of lung cancer patients.
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