M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells

Frontiers in Oncology

Lizhu Lin¹  Yuqi Yang²  Qiu-Xu Teng²  Yi-Ge Fu²  Jing-Quan Wang²  Zi-Ning Lei²  Ketankumar Patel²  Zhuo-Xun Wu²  Zhe-Sheng Chen²  Lili Liu³  Zheng Peng⁴  Chang Zou⁴ 

[1] Cancer Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China;Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States;Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, China;The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen People's Hospital, Shenzhen, China;

关键词: ATP-binding cassette (ABC) transporter;    M3814;    nedisertib;    ABCG2;    multidrug resistance (MDR);   

DOI  :  10.3389/fonc.2020.00674

来源: DOAJ

【 摘 要 】

M3814, also known as nedisertib, is a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor under phase 2 clinical trials. ABCG2 is a member of the ATP-binding cassette (ABC) transporter family that is closely related to multidrug resistance (MDR) in cancer treatment. In this study, we demonstrated that M3814 can modulate the function of ABCG2 and overcome ABCG2-mediated MDR. Mechanistic studies showed that M3814 can attenuate the efflux activity of ABCG2 transporter, leading to increased ABCG2 substrate drugs accumulation. Furthermore, M3814 can stimulate the ABCG2 ATPase activity in a concentration-dependent manner without affecting the ABCG2 protein expression or cell surface localization of ABCG2. Moreover, the molecular docking analysis indicated a high affinity between M3814 and ABCG2 transporter at the drug-binding cavity. Taken together, our work reveals M3814 as an ABCG2 modulator and provides a potential combination of co-administering M3814 with ABCG2 substrate-drugs to overcome MDR.

【 授权许可】

Unknown