miR-100-5p confers resistance to ALK tyrosine kinase inhibitors Crizotinib and Lorlatinib in EML4-ALK positive NSCLC

Lai, Yi Chun; Kacal, Merve; Kanony, Maraam; Stukan, Iga; Jatta, Kenbugul; Kis, Lóránd; Norberg, Erik; Vakifahmetoglu-Norberg, Helin; Lewensohn, Rolf; Ekman, Simon

doi:10.1016/j.bbrc.2019.02.016

Cited by 19 publications

(9 citation statements)

References 24 publications

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“…ALK L1196M primarily existed within the epithelial tumor cells, suggesting that EMT and ALK mutations co-exist as independent mechanisms of drug resistance. EMT was associated with decreased expression of miR-200c and increased expression of ZEB1, leading to cross-resistance of the (94).…”

Section: Lineage Changesmentioning

confidence: 99%

The Resistance Mechanisms and Treatment Strategies for ALK-Rearranged Non-Small Cell Lung Cancer

et al. 2021

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Anaplastic lymphoma kinase (ALK) is a validated molecular target for non-small-cell lung cancer (NSCLC). The use of tyrosine kinase inhibitors (TKIs) has led to significantly improved survival benefits. However, the clinical benefits of targeting ALK using TKIs are limited due to the emergence of drug resistance. The landscape of resistance mechanisms and treatment decisions has become increasingly complex. Therefore, continued research into new drugs and combinatorial therapies is required to improve outcomes in NSCLC. In this review, we explore the resistance mechanisms of ALK TKIs in advanced NSCLC in order to provide a theoretical basis and research ideas for solving the problem of ALK drug resistance.

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Section: Lineage Changesmentioning

confidence: 99%

The Resistance Mechanisms and Treatment Strategies for ALK-Rearranged Non-Small Cell Lung Cancer

et al. 2021

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“…miR-100-5p promoted prostate cancer proliferation, and silencing of miR-100-5p gene enhanced the apoptosis and reverse castration-induced resistance cell cancer [19]. The down regulation of miR-100-5p expression is signi cantly decreased non-small cell lung cancer (NSCLS) proliferation, ability colony-forming and signi cantly enhanced sensitivity of NSCLC cells to rst line of chemotherapeutic drugs (crizotinib, lorlatinib, and cisplatin) [20]. The silencing of miR-100-5p was also observed to increase resensitivity of resistant epithelial ovarian cancer to Cisplatin [16].…”

Section: Discussionmentioning

confidence: 99%

miR-100-5p Enhanced Cell Cycle-mediated Chemoresistance Through Modulating CTDSPL/pRB/E2F1 Signaling Pathway in Oxaliplatin-Resistant Colorectal Cancer

Chen

Singh

et al. 2022

Preprint

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Purpose: miR-100-5p has been found upregulated in Oxaliplatin-resistant LoVo colorectal cell lines, but its function still need further study. Here, we investigated its function in cell regulation chemoresistance in chemoresistant colorectal cancer cell lines.Methods: Microarray, quantitative polymerase chain reaction (qRT-PCR) and westernblot were used to analysis the level of miR-100-5p. The downstream candidate gen target of miR-100-5p, CTDSPL in Oxaliplatin resistant (OXR)-LoVo colorectal cell lines were screened using the different types of bioinformatics based miRNA target prediction data are TargetScan (http://www.targetscan.org/), miRanda (http://www.microrna.org/ and mirTar (http://mirtar.mbc.nctu.edu.tw/human/). CTDSPL, a phosphatase-like tumor suppressor level was detected by westernblot as well with cell cycle progression chemoresistance associated colorectal cancer cell CTDSPL/p-RB/E2F1. Immunofluorescence assay and westernblot showed the cell properties were altered between parental and Oxaliplatin resistant LoVo cell lines. Bioinformatic prediction, (http://alggen.1si.upc.es/cgi-bin/promo_v3) was used to extend the investigation of miR-100-5p upstream regulation through checking dissimilarity index with margin less or equal than 15%, FOXP3, trancription factor forkhead box as upstream target. Interaction between miR-100-5p and CTDSPL regulation was confirmed using mimic miR-100-5p overexpression and knockdown upstream target sh-RNA approach.Results: hsa-miR-100-5p level was found significantly upregulated in LoVo-OXR than parental LoVo cell line, resulted in downregulation CTDSPL as a major target of miR-100-5p. The downregulated of CTDSPL/p-RB/E2F1 promotes cell proliferation and cell cycle progression in LoVo OXR compared with LoVo parental cell lines. Moreover, among various upstream targets FOXP3 is an upstream regulator of miR-100-5p. In addition, mimic miR-100-5p overexpression downregulated CTDSPL/p-RB/E2F1 signaling pathway was reverted upon miR-100-5p inhibition in CRC cell lines.Conclusion: Collectively, miR-100-5p is chemoresistance inducer through modulation of CTDSPL/p-RB/E2F1 signaling pathway in CRC cell. This phenomenon might offer a therapeutic platform for overcoming chemoresistance in cancer treatment.

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“…For instance, miR-100 and miR-873 can confer resistance to ALK tyrosine kinase inhibitors in NSCLC cells. 31,32 MiRNAs have been recognized as a promising target for NSCLC treatment. MiR-15b was reported to function as a tumor promoter in some cancers including NSCLC.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of miR-15b partially reverses the cisplatin resistance of NSCLC through the GSK-3β/MCL-1 pathway

Lu¹,

Lu²,

Jia³

et al. 2021

Adv Clin Exp Med

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Background. Induction of acquired drug resistance occurs frequently with cisplatin-based therapy for non-small cell lung cancer (NSCLC). As recent studies have demonstrated that deregulation of microRNAs (miRNAs) is associated with drug resistance in cancers, correcting the deregulation of miRNAs represents a promising strategy to reverse acquired resistance in NSCLC.Objectives. This study investigated the functional role of miR-15b in cisplatin resistance in NSCLC. Materials and methods.Cisplatin-resistant PC9 and A549 NSCLC cell lines (PC9-R and A549-R) were established through long-term exposure to cisplatin. Differences in miR-15b expression between cisplatin-resistant NSCLC cell lines and their parental cell lines were identified through quantitative real-time polymerase chain reaction (qRT-PCR). The effect of anti-miR-15b on the sensitivity of PC9-R and A549-R to cisplatin-induced cytotoxicity was evaluated using Cell Counting Kit-8 (CCK-8) assays. Regulation of GSK-3β by miR-15b was confirmed with luciferase reporter assays. Cell apoptosis and mitochondrial membrane potential (MMP) were measured using flow cytometry analysis.Results. In PC9-R and A549-R cells, miR-15b was significantly overexpressed. However, knockdown of miR-15b clearly reduced cisplatin resistance in PC9-R and A549-R cells. Researching the mechanism, we proved that GSK-3β was the target of miR-15b. Knockdown of miR-15b significantly increased the expression GSK-3β and thus promoted the degradation of MCL-1, which is a key anti-apoptosis protein. As a result, anti-miR-15b expanded the cisplatin-induced apoptosis in cisplatin-resistant NSCLC cells.Conclusions. Knockdown of miR-15b partially reversed cisplatin resistance in NSCLC cells through the GSK-3β/MCL-1 pathway.

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miR-100-5p confers resistance to ALK tyrosine kinase inhibitors Crizotinib and Lorlatinib in EML4-ALK positive NSCLC

Cited by 19 publications

References 24 publications

The Resistance Mechanisms and Treatment Strategies for ALK-Rearranged Non-Small Cell Lung Cancer

The Resistance Mechanisms and Treatment Strategies for ALK-Rearranged Non-Small Cell Lung Cancer

miR-100-5p Enhanced Cell Cycle-mediated Chemoresistance Through Modulating CTDSPL/pRB/E2F1 Signaling Pathway in Oxaliplatin-Resistant Colorectal Cancer

Knockdown of miR-15b partially reverses the cisplatin resistance of NSCLC through the GSK-3β/MCL-1 pathway

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