TOPK promotes lung cancer resistance to EGFR tyrosine kinase inhibitors by phosphorylating and activating c-Jun.

Ying Li,Ting Wang,Shengqing Li,Shengli Zhang,Shudi Xu,Tao Wang,Zhiwei Yang,Lintao Jia,Mengjie Niu,Weijie Li

doi:10.18632/oncotarget.6826

Abstract

Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have shown promising clinical efficacy in non-squamous non-small cell lung cancer (NSCLC); however, resistance is frequently observed in malignant cells, operating through a mechanism that remains largely unknown. The present study shows that T-lymphokine-activated killer cell-originated protein kinase (TOPK) is upregulated in NSCLC and excessively activated in TKI-refractory cells. TOPK dictates the responsiveness of lung cancers to the EGFR-targeted TKI gefitinib through the transcription factor AP-1 component c-Jun. TOPK binds directly to and phosphorylates c-Jun, which consequently activates the transcription of AP-1 target genes, including CCND1 and CDC2. TOPK silencing sensitizes EGFR-TKI-resistant lung cancer cells to gefitinib and increases gefitinib efficacy in preclinical lung adenocarcinoma xenograft models. These findings represent a novel mechanism of lung cancer resistance to TKIs and suggest that TOPK may have value both as a predictive biomarker and as a therapeutic target: TOPK-targeted therapy may synergize with EGFR-targeted therapy in lung cancers.

Highlights

Lung cancer with distal metastasis has an extremely high mortality rate [1]
We found that T-lymphokine-activated killer www.impactjournals.com/oncotarget cell-originated protein kinase (TOPK) was overexpressed in EGFRTKI-resistant lines (Figure 1C, 1D), including calu-3, H460, H441, H1975, H1650 and A549
One of the molecular mechanisms of EGFRTKI resistance is activation of signaling downstream of epidermal growth factor receptor (EGFR). We found in both A549 and H1975 cells that EGFR activation stimulated by EGF can be blocked by the EGFR-tyrosine kinase inhibitors (TKIs) gefitinib; TOPK phosphorylation occurred downstream of EGF/EGFR and was only partially inhibited by gefitinib (Figure 1E)

Summary

Introduction

Lung cancer with distal metastasis has an extremely high mortality rate [1]. Compared with the limited efficacy of traditional chemo- and radiotherapy in combination with surgery, molecular targeted chemicals, EGFR tyrosine kinase inhibitors (TKIs), have emerged as potent anticancer agents and have significantly improved the prognosis of lung cancer patients with EGFR mutations [2]. Despite great progress in the treatment of lung cancer, resistance to EGFR-TKIs commonly occurs, leading to a modest response rate to first-line TKI therapy or to frequent recurrence after temporarily effective TKI treatment [3, 4]. Investigation of the molecular events that determine the response of lung cancer cells to TKIs is in progress to devise strategies to overcome resistance [5, 6]. Three molecular mechanisms of EGFR-TKI resistance are reported: the EGFR T790M gatekeeper mutation[2], activation of bypass signaling [7,8,9], and activation of downstream signaling [10, 11]. The present study found that upregulation of T-lymphokine-activated killer www.impactjournals.com/oncotarget cell-originated protein kinase (TOPK), a serine/threonine protein kinase, is a new mechanism of resistance to gefitinib downstream of EGFR in NSCLC

Methods

Results

Conclusion