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bioRxiv · 10.1101/851279

Transcriptional activation of cyclin D1 via HER2/HER3 contributes to cell survival and EGFR tyrosine kinase inhibitor resistance in non-small cell lung carcinoma

Liu, B.·Chen, D.·Chen, S.·Saber, A.·Haisma, H. J.
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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-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.

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Liu, B., Chen, D., Chen, S., Saber, A., Haisma, H. J.. 2019-11-21. Transcriptional activation of cyclin D1 via HER2/HER3 contributes to cell survival and EGFR tyrosine kinase inhibitor resistance in non-small cell lung carcinoma. https://doi.org/10.1101/851279

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