Reversal of Cancer Multidrug Resistance (MDR) Mediated by ATP-Binding Cassette Transporter G2 (ABCG2) by AZ-628, a RAF Kinase Inhibitor

Wang, Jingquan; Teng, Quincy; Lei, Zi‐Ning; Ji, Ning; Cui, Qingbin; Fu, Han; Lin, Lizhu; Yang, Dong‐Hua; Fan, Ying-Fang; Chen, Zhe‐Sheng

doi:10.3389/fcell.2020.601400

Cited by 24 publications

(15 citation statements)

References 57 publications

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“…However, the underlying mechanism of how gilteritinib overcomes lorlatinib resistance to the double mutant I1171N/F1174I is incapable of elucidating directly based on the structural comparison of ALK–lorlatinib and ALK–gilteritinib complexes. To address this issue, MD simulations that consider conformational dynamics of proteins were performed to illuminate the effect of double mutations I1171N/F1174I on the conformational plasticity of ALK–lorlatinib and ALK–gilteritinib complexes ( Sora et al, 2020 ; Wang, et al, 2020 ; Zhou et al, 2021 ; Li et al, 2021b ; Ni et al, 2021b ).…”

Section: Results and Discssionmentioning

confidence: 99%

Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase

Liang

Wang

et al. 2021

Front. Cell Dev. Biol.

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Anaplastic lymphoma kinase (ALK) is validated as a therapeutic molecular target in multiple malignancies, such as non-small cell lung cancer (NSCLC). However, the feasibility of targeted therapies exerted by ALK inhibitors is inevitably hindered owing to drug resistance. The emergence of clinically acquired drug mutations has become a major challenge to targeted therapies and personalized medicines. Thus, elucidating the mechanism of resistance to ALK inhibitors is helpful for providing new therapeutic strategies for the design of next-generation drug. Here, we used molecular docking and multiple molecular dynamics simulations combined with correlated and energetical analyses to explore the mechanism of how gilteritinib overcomes lorlatinib resistance to the double mutant ALK I1171N/F1174I. We found that the conformational dynamics of the ALK kinase domain was reduced by the double mutations I1171N/F1174I. Moreover, energetical and structural analyses implied that the double mutations largely disturbed the conserved hydrogen bonding interactions from the hinge residues Glu1197 and Met1199 in the lorlatinib-bound state, whereas they had no discernible adverse impact on the binding affinity and stability of gilteritinib-bound state. These discrepancies created the capacity of the double mutant ALK I1171N/F1174I to confer drug resistance to lorlatinib. Our result anticipates to provide a mechanistic insight into the mechanism of drug resistance induced by ALK I1171N/F1174I that are resistant to lorlatinib treatment in NSCLC.

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Section: Results and Discssionmentioning

confidence: 99%

Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase

Liang

Wang

et al. 2021

Front. Cell Dev. Biol.

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“…Till now, tremendous efforts have been made to explore the mechanism of MDR, mostly by establishing ABC transporter-overexpressing cancer cell lines (9,29). By comparing parental and resistant cancer cell lines using molecular biology and cellular methods, researchers have identified numerous ABC transporter substrates (21,(30)(31)(32)(33)(34) as well as inhibitors (16,(35)(36)(37)(38)(39)(40). Computational strategies were also developed to boost the modulator discovery process especially multitarget modulators (41,42).…”

Section: Discussionmentioning

confidence: 99%

Establishment and Characterization of a Novel Multidrug Resistant Human Ovarian Cancer Cell Line With Heterogenous MRP7 Overexpression

Wang

Yang

et al. 2021

Front. Oncol.

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Ovarian cancer is one of the leading female malignancies which accounts for the highest mortality rate among gynecologic cancers. Surgical cytoreduction followed by chemotherapy is the mainstay of treatment. However, patients with recurrent ovarian cancer are likely to exhibit resistance to chemotherapy due to reduced sensitivity to chemotherapeutic drugs. Adenosine triphosphate (ATP)-binding cassette (ABC) transporters have been extensively studied as multidrug resistance (MDR) mediators since they are responsible for the efflux of various anticancer drugs. Multidrug resistance protein 7 (MRP7, or ABCC10) was discovered in 2001 and revealed to transport chemotherapeutic drugs. Till now, only limited knowledge was obtained regarding its roles in ovarian cancer. In this study, we established an MRP7-overexpressing ovarian cancer cell line SKOV3/MRP7 via transfecting recombinant MRP7 plasmids. The SKOV3/MRP7 cell line was resistant to multiple anticancer drugs including paclitaxel, docetaxel, vincristine and vinorelbine with a maximum of 8-fold resistance. Biological function of MRP7 protein was further determined by efflux-accumulation assays. Additionally, MTT results showed that the drug resistance of the SKOV3/MRP7 cells was reversed by cepharanthine, a known inhibitor of MRP7. Moreover, we also found that the overexpression of MRP7 enhanced the migration and epithelial-mesenchymal transition (EMT) induction. In conclusion, we established an in vitro model of MDR in ovarian cancer and suggested MRP7 overexpression as the leading mechanism of chemoresistance in this cell line. Our results demonstrated the potential relationship between MRP7 and ovarian cancer MDR.

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“…More importantly, we identified the three most significant small molecule drugs, including AZ-628, NVP-AUY922, and Nomifensine, that might improve the survival of LUAD patients, In particular, NVP-AUY622 has the lowest IC50 value in LUAD cell lines. Among these three drugs, AZ-628, an RAF Kinase inhibitor, can reverse cancer multidrug resistance (MDR) by mediating ATP-Binding Cassette Transporter G2 (ABCG2) ( Wang et al, 2020b ). NVP-AUY922 has been found to have potent anti-tumor activity and can inhibit tumor growth, including NSCLC, breast cancer, colorectal cancer, and so on ( Jensen et al, 2008 ; Garon et al, 2013 ; Lee et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Analysis of Genome-Wide Alternative Splicing Profiling and Development of Potential Drugs in Lung Adenocarcinoma

Song

Liu

et al. 2021

Front. Genet.

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Alternative splicing (AS) is significantly related to tumor development as well as a patient’s clinical characteristics. This study was designed to systematically analyze the survival-associated AS signatures in Lung adenocarcinoma (LUAD). Among 30,735 AS events in 9,635 genes, we found that there were 1,429 AS in 1,125 genes which were conspicuously related to the overall survival of LUAD patients. Then, according to the seven types of AS events, we established AS signatures and constructed a new combined prognostic model. The Kaplan-Meier curve results showed that seven types of AS signatures and the combined prognostic model could divide patients into distinct prognoses. The ROC curve shows that all eight AS signatures had powerful predictive properties with different AUCs ranging from 0.708 to 0.849. Additionally, the elevated risk scores were positively related to higher TNM stage and metastasis. Interestingly, AS events and splicing factors (SFs) network shed light on a meaningful connection between prognostic AS genes and corresponding SFs. Moreover, we found that the combined prognostic model signature has a higher predictive ability than the mRNA signature. Furthermore, tumors at high risk might evade immune recognition by decreasing the expression of antigen presentation genes. Finally, we predicted the three most significant small molecule drugs to inhibit LUAD. Among them, NVP-AUY922 had the lowest IC50 value and might become a potential drug to prolong a patient’s survival. In conclusion, our study established a potential prognostic signature for LUAD patients, revealed a splicing network between AS and SFs and possible immune escape mechanism, and provided several small-molecule drugs to inhibit tumorigenesis.

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Reversal of Cancer Multidrug Resistance (MDR) Mediated by ATP-Binding Cassette Transporter G2 (ABCG2) by AZ-628, a RAF Kinase Inhibitor

Cited by 24 publications

References 57 publications

Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase

Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase

Establishment and Characterization of a Novel Multidrug Resistant Human Ovarian Cancer Cell Line With Heterogenous MRP7 Overexpression

Analysis of Genome-Wide Alternative Splicing Profiling and Development of Potential Drugs in Lung Adenocarcinoma

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