Transcriptional activation of cyclin D1 via HER2/HER3 contributes to EGFR-TKI resistance in lung cancer

Bin Liu, Deng Chen, Shipeng Chen, Ali Saber, Hidde Haisma*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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-spheroid 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.

Original languageEnglish
Article number114095
Number of pages13
JournalBiochemical Pharmacology
Volume178
Early online date11-Jun-2020
DOIs
Publication statusPublished - Aug-2020

Keywords

  • ACQUIRED-RESISTANCE
  • RECEPTOR
  • MECHANISMS
  • MUTATIONS
  • GROWTH
  • TARGET
  • TUMORS

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