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MRTX849 Reverses ABCB1-Mediated Multidrug Resistance in Cancer Cells

LU Yongzheng^1#, LIU Baojie^1#, ZHANG Xinyu^2#, DONG Xingduo³, TANG Yaqi¹, LIN Ruihui¹, SHANG Zilin¹, PAN Zhifang^1
*, FENG Weiguo^1
*

( ¹ School of Life Science and Technology, Weifang Medical University, Weifang 261053, China; ²Gastrointestinal Surgery Department, the Second Affiliated Hospital of Shandong First Medical University, Taian 271000, China; ³College of Pharmacy and Health Sciences, St. John’s University, New York 11439, United States)

Abstract:

P-glycoprotein (ABCB1/P-gp) overexpression is one of the major factors leading to MDR (multidrug resistance) in cancers. Therefore, it is important to find effective drugs to overcome ABCB1-mediated MDR. MRTX849 is a mutation-selective KRAS G12C covalent inhibitor for the treatment of non-small cell lung cancer and colorectal cancer. This study aimed to investigate whether MRTX849 could reverse ABCB1-mediated MDR and the underlying mechanism. The results of reversal assay showed that MRTX849 significantly reversed ABCB1- mediated MDR without affecting ABCG2-mediated MDR. The results of Western blot and immunofluorescence assays suggested that MRTX849 did not affect the intracellular expression and localization of ABCB1. Further studies revealed that MRTX849 inhibited ABCB1 efflux function, leading to an increase in intracellular drug accumulation levels, thereby reversing MDR. In addition, molecular docking analysis showed that MRTX849 and ABCB1 presented good affinity. In conclusion, this study demonstrated that MRTX849 reversed ABCB1-mediated MDR, providing a new clinical treatment strategy for chemotherapy-resistant tumor patients.

CSTR: 32200.14.cjcb.2022.12.0004