Kinesin light chain 4 as a new target for lung cancer chemoresistance via targeted inhibition of checkpoint kinases in the DNA repair network

Jeong-Hwa Baek,Jie-Young Song,Sang-Gu Hwang,Jiyeon Ahn,Ju-Young Kim,Jong Kuk Park,Kee-Ho Lee,Chang-Woo Lee,Janet Lee,Hong Shik Yun,Eun Ho Kim,Jae-Sung Kim,Yeon-Joo Lee

doi:10.1038/s41419-020-2592-z

Abstract

The poor therapeutic efficacy of non-small cell lung cancer (NSCLC) is partly attributed to the acquisition of chemoresistance. To investigate the mechanism underlying this resistance, we examined the potential link between kinesin light chain 4 (KLC4), which we have previously reported to be associated with radioresistance in NSCLC, and sensitivity to chemotherapy in human lung cancer cell lines. KLC4 protein levels in lung cancer cells correlated with the degree of chemoresistance to cisplatin treatment. Furthermore, KLC4 silencing enhanced the cytotoxic effect of cisplatin by promoting DNA double-strand breaks and apoptosis. These effects were mediated by interaction with the checkpoint kinase CHK2, as KLC4 knockdown increased CHK2 activation, which was further enhanced in combination with cisplatin treatment. In addition, KLC4 and CHEK2 expression levels showed negative correlation in lung tumor samples from patients, and KLC4 overexpression correlated negatively with survival. Our results indicate a novel link between the KLC4 and CHK2 pathways regulating DNA damage response in chemoresistance, and highlight KLC4 as a candidate for developing lung cancer-specific drugs and customized targeted molecular therapy.

Highlights

Lung cancer is one of the main reasons of cancerrelated deaths worldwide, and 80% cases of lung cancer are non-small cell lung cancer (NSCLC) with poor prognosis at diagnosis and limited therapeutic efficiency[1,2]
We assessed the effect of cisplatin treatment on cell growth and proliferation of the three lung cancer cell lines
To investigate whether cisplatin as a DNA damage inducer altered double strand break (DSB) repair, we attempted to validate DNA damage response (DDR) according to kinesin light chain 4 (KLC4) expression in the lung cancer cell lines

Summary

Introduction

Lung cancer is one of the main reasons of cancerrelated deaths worldwide, and 80% cases of lung cancer are non-small cell lung cancer (NSCLC) with poor prognosis at diagnosis and limited therapeutic efficiency[1,2]. Current research directions for lung cancer treatment are inclusive of immunotherapy, which makes it possible for the body’s immune system to attack the tumor cells, epigenetics, and new combinations of chemotherapy and radiotherapy, both on their own and collectively. Many of these new treatments work through immune checkpoint blockade, disrupting cancer’s. CHK1 and CHK2 play critical roles in the DNA damage response (DDR) network[11], and DNA repair pathways are important for resistance to DNA-damaging cytotoxic therapy and radiation[12]. Low level of CHK2 in lung cancers was suggested to contribute to chemo-radiation resistance[19]

Objectives

Methods

Results

Conclusion