Combination therapy of gefitinib and miR-30a-5p may overcome acquired drug resistance through regulating the PI3K/AKT pathway in non-small cell lung cancer

Wang, Fengfeng; Meng, Fei; Wong, Sze Chuen Cesar; Cho, William C.; Yang, Shaofeng; Chan, Lawrence

doi:10.1177/1753466620915156

Cited by 25 publications

(16 citation statements)

References 56 publications

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“…In addition, ERK and Akt signaling pathways are usually associated with proliferation and drug resistance of human cancer cells, including NSCLC cells. [41][42][43][44] Zeng et al reported that miR-222 inhibited the cisplatin sensitivity in bladder cancer cells via activation of Akt signaling by targeting PPP2R2A. 45 Consistent with previous studies, our data indicated that exosomal miR-136-5p promoted NSCLC cell proliferation and anlotinib resistance by targeting PPP2R2A and activation of Akt signaling pathway.…”

supporting

confidence: 90%

Exosomal miR-136-5p Derived from Anlotinib-Resistant NSCLC Cells Confers Anlotinib Resistance in Non-Small Cell Lung Cancer Through Targeting PPP2R2A

Gu¹,

Hu²,

Hui³

et al. 2021

IJN

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Background: Anlotinib resistance is a challenge for advanced non-small cell lung cancer (NSCLC). Understanding the underlying mechanisms against anlotinib resistance is of great importance to improve prognosis and treatment of patients with advanced NSCLC. Methods: RT-qPCR assay was used to assess the level of miR-136-5p in anlotinib-resistant NSCLC cells and exosomes derived from anlotinib-resistant NSCLC cells. In addition, miR-136-5p level in tumor tissues from patients who exhibited a poor response to anlotinib therapy and patients who were therapy naïve or patients who exhibited a positive response to anlotinib therapy was detected by RT-qPCR assay. Results: In this study, we found that high levels of plasma exosomal miR-136-5p is correlated with clinically poor anlotinib response. In addition, anlotinib-resistant NSCLC cells promoted parental NSCLC cell proliferation via transferring functional miR-136-5p from anlotinib-resistant NSCLC cells to parental NSCLC cells via exosomes. Moreover, exosomal miR-136-5p could endow NSCLC cells with anlotinib resistance by targeting PPP2R2A, leading to the activation of Akt pathway. Furthermore, miR-136-5p antagomir packaging into anlotinib-resistant NSCLC cell-derived exosomes functionally restored NSCLC cell anlotinib sensitivity in vitro. Animal studies showed that A549/anlotinib cellderived exosomal miR-136-5p agomir promoted A549 cell anlotinib resistance in vivo. Conclusion: Collectively, these findings indicated that anlotinib-resistant NSCLC cellderived exosomal miR-136-5p confers anlotinib resistance in NSCLC cells by targeting PPP2R2A, indicating miR-136-5p may act as a potential biomarker for anlotinib response in NSCLC.

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supporting

confidence: 90%

Exosomal miR-136-5p Derived from Anlotinib-Resistant NSCLC Cells Confers Anlotinib Resistance in Non-Small Cell Lung Cancer Through Targeting PPP2R2A

Gu¹,

Hu²,

Hui³

et al. 2021

IJN

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“…Of note, dual inhibitors of IGF1R and EGFR markedly decreased p-AKT and p-ERK expression levels compared with the control group in H1650GR (H1650-acquired gefitinib-resistance), H460, and H1975 cell lines. miR-30a-5p mimics, along with repressing PI3K expression, can induce cell apoptosis, suppress cell invasion and migration in the treated H1650GR cell line [220][221][222][223][224]. Compared to gefitinib-sensitive cell line PC9, miR-133a-3p was significantly downregulated in PC9/GR cell line, and miR-133a-3p overexpression increased the NSCLC cells' sensitivity to gefitinib and vice versa.…”

Section: Gefitinibmentioning

confidence: 96%

Cell Behavior of Non-Small Cell Lung Cancer Is at EGFR and MicroRNAs Hands

Ibrahim

Abdel-Mawgood

2021

IJMS

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Lung cancer is a complex disease associated with gene mutations, particularly mutations of Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) and epidermal growth factor receptor (EGFR). Non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are the two major types of lung cancer. The former includes most lung cancers (85%) and are commonly associated with EGFR mutations. Several EGFR-tyrosine kinase inhibitors (EGFR-TKIs), including erlotinib, gefitinib, and osimertinib, are effective therapeutic agents in EGFR-mutated NSCLC. However, their effectiveness is limited by the development (acquired) or presence of intrinsic drug resistance. MicroRNAs (miRNAs) are key gene regulators that play a profound role in the development and outcomes for NSCLC via their role as oncogenes or oncosuppressors. The regulatory role of miRNA-dependent EGFR crosstalk depends on EGFR signaling pathway, including Rat Sarcoma/Rapidly Accelerated Fibrosarcoma/Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase 1/2 (Ras/Raf/MEK/ERK1/2), Signal Transducer and Activator of Transcription (STAT), Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-kB), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), Janus kinase 1 (JAK1), and growth factor receptor-bound protein 2 (GRB2). Dysregulated expression of miRNAs affects sensitivity to treatment with EGFR-TKIs. Thus, abnormalities in miRNA-dependent EGFR crosstalk can be used as diagnostic and prognostic markers, as well as therapeutic targets in NSCLC. In this review, we present an overview of miRNA-dependent EGFR expression regulation, which modulates the behavior and progression of NSCLC.

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“…Illustratively, Wang et al. ( 155 ) studied the combination of miR-30a-5p with gefitinib to overcome drug resistance via regulation of the insulin-like growth factor receptor-1 (IGF1R) and hepatocyte growth factor receptor signaling pathways in NSCLC both in vitro and in vivo . Liang et al.…”

Section: Mirna Therapeutics and Their Adjuvant Potential Against Angiogenesismentioning

confidence: 99%

“…Illustratively, Wang et al (155) studied the combination of miR-30a-5p with gefitinib to overcome drug resistance via regulation of the insulin-like growth factor receptor-1 (IGF1R) and hepatocyte growth factor receptor signaling pathways in NSCLC both in vitro and in vivo. Liang et al (156) formulated exosomes to simultaneously deliver the anticancer drug 5-FU and a miR-21 inhibitor oligonucleotide (miR-21i) to 5-FUresistant colon cancer cells.…”

Section: Mirna Therapeutics and Their Adjuvant Potential Against Angiogenesismentioning

confidence: 99%

MiRNAs as Anti-Angiogenic Adjuvant Therapy in Cancer: Synopsis and Potential

Lahooti¹,

Poudel

Mikelis³

et al. 2021

Front. Oncol.

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Angiogenesis is a key mechanism for tumor growth and metastasis and has been a therapeutic target for anti-cancer treatments. Intensive vascular growth is concomitant with the rapidly proliferating tumor cell population and tumor outgrowth. Current angiogenesis inhibitors targeting either one or a few pro-angiogenic factors or a range of downstream signaling molecules provide clinical benefit, but not without significant side effects. miRNAs are important post-transcriptional regulators of gene expression, and their dysregulation has been associated with tumor progression, metastasis, resistance, and the promotion of tumor-induced angiogenesis. In this mini-review, we provide a brief overview of the current anti-angiogenic approaches, their molecular targets, and side effects, as well as discuss existing literature on the role of miRNAs in angiogenesis. As we highlight specific miRNAs, based on their activity on endothelial or cancer cells, we discuss their potential for anti-angiogenic targeting in cancer as adjuvant therapy and the importance of angiogenesis being evaluated in such combinatorial approaches.

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Combination therapy of gefitinib and miR-30a-5p may overcome acquired drug resistance through regulating the PI3K/AKT pathway in non-small cell lung cancer

Cited by 25 publications

References 56 publications

Exosomal miR-136-5p Derived from Anlotinib-Resistant NSCLC Cells Confers Anlotinib Resistance in Non-Small Cell Lung Cancer Through Targeting PPP2R2A

Exosomal miR-136-5p Derived from Anlotinib-Resistant NSCLC Cells Confers Anlotinib Resistance in Non-Small Cell Lung Cancer Through Targeting PPP2R2A

Cell Behavior of Non-Small Cell Lung Cancer Is at EGFR and MicroRNAs Hands

MiRNAs as Anti-Angiogenic Adjuvant Therapy in Cancer: Synopsis and Potential

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