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

doi:10.1016/j.bcp.2020.114095

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.

Highlights

Lung cancer is the leading cause of cancer mortality worldwide
Since we showed that HER2 and HER3 were upregulated in EGFR19del disrupted and ER cells, we speculated that suppression of HER2 and HER3 may further inhibit tyrosine kinase activity and tumor proliferation
We found that HER2/HER3 complex bound more to the cyclin D1 (CCND1) promoter in HCC827ER and H1650 Epidermal growth factor receptor (EGFR)−/− cells than in original cell lines (Fig. 7A)

Summary

Introduction

Lung cancer is the leading cause of cancer mortality worldwide. In 2018, more than 2 million new cases and 1.7 million lung cancer-related deaths were reported [1]. Non-small cell lung carcinoma (NSCLC) is the main type of lung cancer, accounting for 85% of all lung cancer cases [2]. Surgery or surgery followed by chemotherapy is the common choice for patients with resectable lung cancer. For those with advanced stage cancer, targeted therapy can be used to achieve a longer progression-free survival [2]. Tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, and afatinib, are the commonly used targeted agents for NSCLC patients with certain EGFR mutations [3,4]. 10% of NSCLC patients from Western countries and 30% of NSCLC patients from East Asia, harboring EGFR-

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