P-glycoprotein Mediates Resistance to the Anaplastic Lymphoma Kinase Inhibitor Ensartinib in Cancer Cells

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.

Docosahexaenoic Acid, a Key Compound for Enhancing Sensitization to Drug in Doxorubicin-Resistant MCF-7 Cell Line

“…Downregulation of P-glycoprotein (P-gp) and Transglutaminase 2 (TG2) has been identified as a potential mechanism to sensitize drug-resistant breast cancer cells to chemotherapy [ 66 ]. These two proteins are known to be overexpressed in many drug-resistant cancer cells, leading to increased drug efflux and decreased drug accumulation, thereby reducing the effectiveness of chemotherapy [ 66 , 67 , 68 , 69 , 70 ]. One mechanism by which drug accumulation can be enhanced is by inhibiting drug efflux transporters, which are proteins that pump drugs out of cancer cells and decrease drug accumulation [ 70 , 71 , 72 , 73 ].…”

Prediction of Drug–Drug Interactions with Ensartinib as a Time-Dependent CYP3A Inhibitor Using Physiologically Based Pharmacokinetic Model

“…One concern in our model development is the omission of transporter influence, particularly the impact of P-gp, despite ensartinib being identified as a potential substrate and inhibitor of P-gp (Vagiannis et al, 2020;Wu et al, 2022). Although P-gp is present in various organs, its contribution to overall drug absorption is quantitatively significant only in specific scenarios, such as very small oral doses or drugs with slow dissolution and diffusion rates (Lin and Yamazaki, 2003).…”

“…The minimal PBPK model was chosen in the distribution module, as it provided a better fit to the observed clinical data compared to the full PBPK model. Although ensartinib has been reported as a potential substrate of P-gp as well as inhibitor of P-gp and ABCG2 (Vagiannis et al, 2020;Wu et al, 2022), the model structure was simplified in this study to focus on the effect of ensartinib on CYP450 enzymes.…”

Anti-Angiogenic Therapy in ALK Rearranged Non-Small Cell Lung Cancer (NSCLC)

“…Combination approaches, however, should be cognizant of bioavailability and potential pharmacokinetic interactions. In particular, the drug efflux functions of P-glycoprotein and ATP-binding cassette super-family G member 2 (ABCG2) may be important for the bioavailability and distribution of ALK and VEGF TKIs [ 34 , 35 , 36 , 37 ].…”