Dual TTK/CLK2 inhibitor, CC-671, selectively antagonizes ABCG2-mediated multidrug resistance in lung cancer cells

Wu, Zhuo-Xun1; Yang, Yuqi1; Wang, Guangsuo2; Wang, Jing-Quan1; Teng, Qiu-Xu1; Sun, Lingling3; Lei, Zi-Ning1; Lin, Lizhu3; Chen, Zhe-Sheng1; Zou, Chang2,4

2020-06-29

10.1111/cas.14505

CANCER SCIENCE   影响因子和分区

1347-9032

1349-7006

One pivotal factor that leads to multidrug resistance (MDR) is the overexpression of ABCG2. Therefore, tremendous effort has been devoted to the search of effective reversal agents to overcome ABCG2-mediated MDR. CC-671 is a potent and selective inhibitor of both TTK (human protein kinase monopolar spindle 1 [hMps1]) and CDC like kinase 2 (CLK2). It represents a new class of cancer therapeutic drugs. In this study, we show that CC-671 is an effective ABCG2 reversal agent that enhances the efficacy of chemotherapeutic drugs in ABCG2-overexpressing lung cancer cells. Mechanistic studies show that the reversal effect of CC-671 is primarily attributed to the inhibition of the drug efflux activity of ABCG2, which leads to an increased intracellular level of chemotherapeutic drugs. In addition, CC-671 does not alter the protein expression or subcellular localization of ABCG2. The computational molecule docking analysis suggests CC-671 has high binding affinity to the drug-binding site of ABCG2. In conclusion, we reveal the interaction between CC-671 and ABCG2, providing a rationale for the potential combined use of CC-671 with ABCG2 substrate to overcome MDR.

ABCG2 CC-671 dual TTK CLK2 inhibitor lung cancer multidrug resistance

SCI

英语

通讯

Shenzhen Economic and Information Committee "Innovation Chain and Industry Chain" integration special support plan project[20180225112449943] ; Science and Technology Foundation of Shenzhen[JCYJ20170412155231633][JCYJ20180305164128430]

Oncology

Oncology

WOS:000543917200001

WILEY

CLINICAL MEDICINE

Web of Science

1.St Johns Univ, Dept Pharmaceut Sci, Coll Pharm & Hlth Sci, Queens, NY 11439 USA
2.Jinan Univ, Clin Med Coll 2, Southern Univ Sci & Technol, Shenzhen Peoples Hosp,Affiliated Hosp 1, Shenzhen, Peoples R China
3.Guangzhou Univ Chinese Med, Affiliated Hosp 1, Canc Ctr, Guangzhou, Peoples R China
4.Jinan Univ, Shenzhen Publ Serv Platform Tumor Precis Med & Mo, Shenzhen Peoples Hosp, Clin Med Coll 2, Shenzhen, Peoples R China

Wu, Zhuo-Xun,Yang, Yuqi,Wang, Guangsuo,et al. Dual TTK/CLK2 inhibitor, CC-671, selectively antagonizes ABCG2-mediated multidrug resistance in lung cancer cells[J]. CANCER SCIENCE,2020,111(8):2872-2882.

Wu, Zhuo-Xun.,Yang, Yuqi.,Wang, Guangsuo.,Wang, Jing-Quan.,Teng, Qiu-Xu.,...&Zou, Chang.(2020).Dual TTK/CLK2 inhibitor, CC-671, selectively antagonizes ABCG2-mediated multidrug resistance in lung cancer cells.CANCER SCIENCE,111(8),2872-2882.

Wu, Zhuo-Xun,et al."Dual TTK/CLK2 inhibitor, CC-671, selectively antagonizes ABCG2-mediated multidrug resistance in lung cancer cells".CANCER SCIENCE 111.8(2020):2872-2882.