Reversal of ABCG2-mediated drug resistance by Tinodasertib (ETC-206)

HAIGAN YANG^1,2Zheshen Li¹Zhuo-Xun Wu¹Xiang Chen¹Letao Bo¹Harsh Patel¹Bohan Zhang¹Wenjun Xiong²Wei Wang^2*Zhe-Sheng Chen^1*

• ¹Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, newyork, United States
• ²The First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China

The development of multidrug resistance (MDR) in cancer therapy, primarily driven by the overexpression of ATP-binding cassette (ABC) transporters, especially ABCG2, poses a significant challenge by greatly reducing the effectiveness of chemotherapy. Tinodasertib (ETC-206), an ATPcompetitive inhibitor specifically targeting MNK1/2 kinases, is under phase 2 clinical trial. In this study, we explored the effects of tinodasertib in overcoming MDR mediated by ABCG2 in both monolayer cancer cells and multicellular tumor spheroids. Our findings demonstrate that tinodasertib significantly enhances the cytotoxicity of ABCG2 substrates, such as mitoxantrone and topotecan, in ABCG2-overexpressing cancer cells, while exhibiting minimal effects on non-resistant parental cells or non-ABCG2 substrates like cisplatin. Mechanistic studies revealed that tinodasertib reverses MDR by blocking the drug efflux function of ABCG2 while leaving its protein levels and subcellular distribution unchanged. ATPase assays and in silico docking studies indicated that tinodasertib interacts with the ABCG2 transporter, predominantly inhibiting its ATPase activity in a concentration-dependent manner. This inhibition suggests that tinodasertib disrupts the ATP hydrolysis process necessary for the transporter's drug efflux function. These findings highlight tinodasertib's potential to antagonize ABCG2-mediated MDR at clinically achievable concentrations. The use of tinodasertib in combination with ABCG2 substrate drugs could provide a novel and effective strategy to overcome MDR in cancer therapy, improving the efficacy of chemotherapy in patients with ABCG2-overexpressing tumors.