P-glycoprotein Mediates Resistance to the Anaplastic Lymphoma Kinase Inhibitor Ensartinib in Cancer Cells
Year: 2022
Type: article
Abstract: Ensartinib (X-396) is a promising second-generation small-molecule inhibitor of anaplastic lymphoma kinase (ALK) that was developed for the treatment of ALK-positive non-small-cell lung cancer. Preclinical and clinical trial results for ensartinib showed superior efficacy and a favorable safety profile compared to the first-generation ALK inhibitors that have been approved by the U.S. Food and Drug Administration. Although the potential mechanisms of acquired resistance to ensartinib have not been reported, the inevitable emergence of resistance to ensartinib may limit its therapeutic application in cancer. In this work, we investigated the interaction of ensartinib with P-glycoprotein (P-gp) and ABCG2, two ATP-binding cassette (ABC) multidrug efflux transporters that are commonly associated with the development of multidrug resistance in cancer cells. Our results revealed that P-gp overexpression, but not expression of ABCG2, was associated with reduced cancer cell susceptibility to ensartinib. P-gp directly decreased the intracellular accumulation of ensartinib, and consequently reduced apoptosis and cytotoxicity induced by this drug. The cytotoxicity of ensartinib could be significantly reversed by treatment with the P-gp inhibitor tariquidar. In conclusion, we report that ensartinib is a substrate of P-gp, and provide evidence that this transporter plays a role in the development of ensartinib resistance. Further investigation is needed.
Source: Cancers
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,513
Awards: G2225267628, G2469234437, G290059146, G2962109343, G3083550356, G3221931586, G3240529281, G3354665758, Study on the Role of Structural Fragments Play in the Transporting Mechanism of P-Glycoprotein, G3890728273, G399578364, G4167383618, G4239120916, G4290021050, G5236293262, G5298540682, G5306925364, G5322946715, Investigation on the Role of Placental Soluble Epoxide Hydrolase in Pregnancies Complicated by Pre-Gestational and Gestational Diabetes Mellitus, G5469664738, G5566489090, G7762680530, G8004836276, G8697812290, A Systematic Approach to Identify Novel Inhibitors of Multidrug-Resistance Associated Proteins from Purified Natural Products: Drug Screening, in Vitro and in Vivo Model Systems
OpenAlex ID: W4229450666