Overcoming Multidrug Resistance by Base-Editing-Induced Codon Mutation

He-Hua Zhang; Jian Xiang; Bin-Cheng Yin; Bang-Ce Ye

doi:10.1021/acsptsci.3c00037

Overcoming Multidrug Resistance by Base-Editing-Induced Codon Mutation

ACS Pharmacol Transl Sci. 2023 Apr 25;6(5):812-819. doi: 10.1021/acsptsci.3c00037. eCollection 2023 May 12.

Authors

He-Hua Zhang¹, Jian Xiang¹, Bin-Cheng Yin^{1

2}, Bang-Ce Ye^{1

2

3}

Affiliations

¹ Lab of Biosystem and Microanalysis, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, Shanghai 200237, China.
² Institute of Engineering Biology and Health, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, Zhejiang, China.
³ School of Chemistry and Chemical Engineering, Shihezi University, Shihezi 832000, Xinjiang, China.

Abstract

Multidrug resistance (MDR) is the main obstacle in cancer chemotherapy. ATP binding cassette (ABC) transporters on the MDR cell membrane can transport a wide range of antitumor drugs out of cells, which is one of the main causes of MDR. Therefore, disturbing ABC transporters becomes the key to reversing MDR. In this study, we implement a cytosine base editor (CBE) system to knock out the gene encoding ABC transporters by base editing. When the CBE system works in MDR cells, the MDR cells are manipulated, and the genes encoding ABC transporters can be inactivated by precisely changing single in-frame nucleotides to induce stop (iSTOP) codons. In this way, the expression of ABC efflux transporters is reduced and intracellular drug retention is significantly increased in MDR cells. Ultimately, the drug shows considerable cytotoxicity to the MDR cancer cells. Moreover, the substantial downregulation of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) implies the successful application of the CBE system in the knockout of different ABC efflux transporters. The recovery of chemosensitivity of MDR cancer cells to the chemotherapeutic drugs revealed that the system has a satisfactory universality and applicability. We believe that the CBE system will provide valuable clues for the use of CRISPR technology to defeat the MDR of cancer cells.