Abstract
M3814, also known as nedisertib, is a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor under phase 2 clinical trials. ABCG2 is a member of the ATP-binding cassette (ABC) transporter family that is closely related to multidrug resistance (MDR) in cancer treatment. In this study, we demonstrated that M3814 can modulate the function of ABCG2 and overcome ABCG2-mediated MDR. Mechanistic studies showed that M3814 can attenuate the efflux activity of ABCG2 transporter, leading to increased ABCG2 substrate drugs accumulation. Furthermore, M3814 can stimulate the ABCG2 ATPase activity in a concentration-dependent manner without affecting the ABCG2 protein expression or cell surface localization of ABCG2. Moreover, the molecular docking analysis indicated a high affinity between M3814 and ABCG2 transporter at the drug-binding cavity. Taken together, our work reveals M3814 as an ABCG2 modulator and provides a potential combination of co-administering M3814 with ABCG2 substrate-drugs to overcome MDR.
Highlights
Lung cancer remains the leading cause of cancer-related mortality worldwide [1]
The reversal effect was evaluated in the presence of an ABCG2 substrate drug, mitoxantrone or doxorubicin
M3814 did not affect the antiproliferative effect of cisplatin, a drug that is not a substrate of ABCG2, in neither drug-sensitive NCIH460 nor drug-resistant NCI-H460/MX20 cells (Figure 1H)
Summary
Lung cancer remains the leading cause of cancer-related mortality worldwide [1]. 85% of the cases are characterized as non-small cell lung cancer (NSCLC) [2]. The clinical treatment strategies include surgery, radiotherapy, and chemotherapy [3]. Paclitaxel, docetaxel, gemcitabine, and irinotecan, has been accepted as standard treatment especially for patients with advanced NSCLC [4, 5]. Another promising option is the usage of small-molecule inhibitors such as gefitinib and erlotinib [6]. The high rate of metastasis and drug resistance maintains the continued high mortality rates of lung cancer
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