Epidermal Growth Factor Receptor Inhibitor Mobocertinib Resensitizes Multidrug-Resistant Cancer Cells by Attenuating the Human ATP-Binding Cassette Subfamily B Member 1 and Subfamily G Member 2.
Yen-Ching LiSung-Han HsiaoMegumi MurakamiYang-Hui HuangYu-Tzu ChangTai-Ho HungYu-Shan WuSuresh V AmbudkarChung-Pu WuPublished in: ACS pharmacology & translational science (2023)
ATP-binding cassette (ABC) transporters, notably ABCB1 (P-glycoprotein) and ABCG2, play a crucial role in the development of multidrug resistance (MDR) during the administration of chemotherapy for cancer patients. With a lack of approved treatments for addressing multidrug-resistant cancers, MDR remains a substantial challenge to the effective management of cancer. Rather than focusing on developing novel synthetic inhibitors, a promising approach to combat MDR involves repurposing approved therapeutic agents to enhance the sensitivity to cytotoxic antiproliferative drugs of multidrug-resistant cancer cells with high expression of ABCB1 or ABCG2. In this investigation, we observed a substantial reversal of MDR conferred by ABCB1 and ABCG2 in multidrug-resistant cancer cells through the use of mobocertinib, an approved third-generation inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. Mobocertinib demonstrated the ability to hinder drug transport function without causing changes in protein expression. The interactions between mobocertinib and ABCB1, as well as ABCG2, were validated through ATPase assays. Furthermore, in silico docking simulations were utilized to substantiate the binding of mobocertinib within the drug-binding pockets of both ABCB1 and ABCG2. We conclude that further testing of mobocertinib in combination therapy is warranted for patients with tumors expressing elevated levels of the ABC drug transporters ABCB1 and ABCG2.
Keyphrases
- multidrug resistant
- epidermal growth factor receptor
- tyrosine kinase
- drug resistant
- gram negative
- acinetobacter baumannii
- advanced non small cell lung cancer
- combination therapy
- klebsiella pneumoniae
- papillary thyroid
- cancer stem cells
- binding protein
- molecular dynamics
- endothelial cells
- drug administration
- dna binding
- squamous cell
- drug induced
- adverse drug
- lymph node metastasis
- small cell lung cancer
- poor prognosis
- young adults
- childhood cancer
- locally advanced
- cystic fibrosis
- radiation therapy
- emergency department
- single cell
- induced pluripotent stem cells
- rectal cancer
- protein protein
- endoplasmic reticulum