Abstract
Several different mechanisms are implicated in the resistance of lung cancer cells to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), and only few have been functionally investigated. Here, using genetically knocked out EGFR and TKI-resistant lung cancer cells, we show that loss of wild-type EGFR attenuates cell proliferation, migration and 3D-spherid formation, whereas loss of mutant EGFR or resistance to TKIs reinforces those processes. Consistently, disruption of wild-type EGFR leads to suppression of HER2/HER3, while mutant EGFR ablation or resistance to TKIs increases HER2/HER3 expression, compensating for EGFR loss. Furthermore, HER2/HER3 nuclear translocation mediates overexpression of cyclin D1, leading to tumor cell survival and drug resistance. Cyclin D1/CDK4/6 inhibition resensitizes erlotinib-resistant (ER) cells to erlotinib. Analysis of cyclin D1 expression in patients with non-small cell lung carcinoma (NSCLC) showed that its expression is negatively associated with overall survival and disease-free survival. Our results provide biological and mechanistic insights into targeting EGFR and TKI resistance.
Abbreviations
- Co-IP
- Co-immunoprecipitation
- CHIP
- Chromatin immunoprecipitation
- CRISPR
- Clustered Regularly Interspaced Short Palindromic Repeats
- ER
- Elortinib resistance
- EGFR
- Epidermal growth factor receptor
- EGFR19del
- Epidermal growth factor receptor exon 19 deletion
- EGFR-/-
- EGFR knockout
- NSCLC
- Non-small cell lung carcinoma
- OS
- overall survival
- DFS
- disease-free survival
- pEGFR
- phosphorylated epidermal growth factor receptor
- STAT3
- Signal transducer and activator of transcription 3
- TCGA
- The Cancer Genome Atlas
- TKI
- Tyrosine kinase inhibitor