Furmonertinib, a Third-Generation EGFR Tyrosine Kinase Inhibitor, Overcomes Multidrug Resistance through Inhibiting ABCB1 and ABCG2 in Cancer Cells.
Chung-Pu WuYen-Ching LiMegumi MurakamiSung-Han HsiaoYun-Chieh LeeYang-Hui HuangYu-Tzu ChangTai-Ho HungYu-Shan WuSuresh V AmbudkarPublished in: International journal of molecular sciences (2023)
ATP-binding cassette transporters, including ABCB1 (P-glycoprotein) and ABCG2 (BCRP/MXR/ABCP), are pivotal in multidrug resistance (MDR) development in cancer patients undergoing conventional chemotherapy. The absence of approved therapeutic agents for multidrug-resistant cancers presents a significant challenge in effectively treating cancer. Researchers propose repurposing existing drugs to sensitize multidrug-resistant cancer cells, which overexpress ABCB1 or ABCG2, to conventional anticancer drugs. The goal of this study is to assess whether furmonertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor overcomes drug resistance mediated by ABCB1 and ABCG2 transporters. Furmonertinib stands out due to its ability to inhibit drug transport without affecting protein expression. The discovery of this characteristic was validated through ATPase assays, which revealed interactions between furmonertinib and ABCB1/ABCG2. Additionally, in silico docking of furmonertinib offered insights into potential interaction sites within the drug-binding pockets of ABCB1 and ABCG2, providing a better understanding of the underlying mechanisms responsible for the reversal of MDR by this repurposed drug. Given the encouraging results, we propose that furmonertinib should be explored as a potential candidate for combination therapy in patients with tumors that have high levels of ABCB1 and/or ABCG2. This combination therapy holds the potential to enhance the effectiveness of conventional anticancer drugs and presents a promising strategy for overcoming MDR in cancer treatment.
Keyphrases
- multidrug resistant
- combination therapy
- epidermal growth factor receptor
- drug resistant
- gram negative
- acinetobacter baumannii
- cancer stem cells
- tyrosine kinase
- papillary thyroid
- patients undergoing
- klebsiella pneumoniae
- systematic review
- small cell lung cancer
- randomized controlled trial
- drug induced
- high throughput
- advanced non small cell lung cancer
- small molecule
- human health
- emergency department
- squamous cell
- signaling pathway
- lymph node metastasis
- squamous cell carcinoma
- radiation therapy