2. Academic Validation
  3. M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells

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

  • Front Oncol. 2020 May 12:10:674. doi: 10.3389/fonc.2020.00674.
Zhuo-Xun Wu 1,  Zheng Peng 2,  Yuqi Yang 1,  Jing-Quan Wang 1,  Qiu-Xu Teng 1,  Zi-Ning Lei 1,  Yi-Ge Fu 1,  Ketankumar Patel 1,  Lili Liu 3,  Lizhu Lin 4,  Chang Zou 2,  Zhe-Sheng Chen 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.
  • 2 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.
  • 3 Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, China.
  • 4 Cancer Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
PMID: 32477940 DOI: 10.3389/fonc.2020.00674
Abstract

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.

Keywords

ABCG2; ATP-binding cassette (ABC) transporter; M3814; multidrug resistance (MDR); nedisertib.

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