The TGFβ–miR200–MIG6 Pathway Orchestrates the EMT-Associated Kinase Switch That Induces Resistance to EGFR Inhibitors

Izumchenko, Eugene; Chang, Xiaofei; Michailidi, Christina; Kagohara, Luciane T.; Ravi, Rajani; Paz, Keren; Brait, Mariana; Hoque, Mohammad O.; Ling, Shizhang; Bedi, Atul; Sidransky, David

doi:10.1158/0008-5472.can-14-0110

Cited by 113 publications

(101 citation statements)

References 41 publications

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“…Despite having lower EGFR activation, cells overexpressing Mig6 show higher Akt phosphorylation through activation of EGFRindependent tyrosine kinases and thereby increase their survival. Furthermore, elevated Mig6/miR-200c ratio is found to be associated with erlotinib resistance in a panel of 25 tumor cell lines and in patient-derived xenografts (PDXs) of NSCLC and pancreatic cancer [87]. Introduction of miR-200c to bladder cancer cells results in complete reversal of resistance against anti-EGFR therapies mainly through Mig6 downregulation, which in turn leads to increased surface levels of EGF receptors, thus making the anti-EGFR therapy more effective in inhibiting the signal [83].…”

Section: Mir-200c Emt and Targeted Therapy Resistancementioning

confidence: 99%

“…Recent data showed that miR-200c negatively regulates KRAS as well, resulting in inhibition of both PI3K/Akt and MAPK pathways in breast and lung cancer cells [58,93]. TGF-β-induced expression of ZEB transcription factors downregulates miR-200c resulting in reduced EGFR activity due to upregulation of Mig6 and confers EMT [87]. On the contrary, TGF-β-induced upregulation of miR-200c has been shown in diabetic nephropathy where miR-200c targets FOG2, which is a negative regulator of the PI3K/Akt pathway [94].…”

Section: Mir-200c Regulation Of Signaling Pathwaysmentioning

confidence: 99%

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miR-200c: a versatile watchdog in cancer progression, EMT, and drug resistance

et al. 2016

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MicroRNAs (miRNAs) are 20-22-nucleotide small endogenous non-coding RNAs which regulate gene expression at post-transcriptional level. In the last two decades, identification of almost 2600 miRNAs in human and their potential to be modulated opened a new avenue to target almost all hallmarks of cancer. miRNAs have been classified as tumor suppressors or oncogenes depending on the phenotype they induce, the targets they modulate, and the tissue where they function. miR-200c, an illustrious tumor suppressor, is one of the highly studied miRNAs in terms of development, stemness, proliferation, epithelial-mesenchymal transition (EMT), therapy resistance, and metastasis. In this review, we first focus on the regulation of miR-200c expression and its role in regulating EMT in a ZEB1/E-cadherin axis-dependent and ZEB1/E-cadherin axis-independent manner. We then describe the role of miR-200c in therapy resistance in terms of multidrug resistance, chemoresistance, targeted therapy resistance, and radiotherapy resistance in various cancer types. We highlight the importance of miR-200c at the intersection of EMT and chemoresistance. Furthermore, we show how miR-200c coordinates several important signaling cascades such as TGF-β signaling, PI3K/Akt signaling, Notch signaling, VEGF signaling, and NF-κB signaling. Finally, we discuss miR-200c as a potential prognostic/diagnostic biomarker in several diseases, but mainly focusing on cancer and its potential application in future therapeutics.

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Section: Mir-200c Emt and Targeted Therapy Resistancementioning

confidence: 99%

Section: Mir-200c Regulation Of Signaling Pathwaysmentioning

confidence: 99%

miR-200c: a versatile watchdog in cancer progression, EMT, and drug resistance

et al. 2016

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“…TGF-β triggers EMT and allow the cells to become invasive (50) (Figure 2). Furthermore, transient TGF-β-stimulation induces EMT and acquired resistance to EGFR-TKIs in NSCLC cell lines (51)(52)(53). TGF-β is the most studied © Translational lung cancer research.…”

Section: Tgf-βmentioning

confidence: 99%

“…During treatment with EGFR-TKIs EMT may be initiated in the tumor cells, resembling a partial EMT. This could be caused by increased expression of TGF-β (52). Surprisingly, drug-withdrawal may further enhance the EMT state due to an EGFR-mediated boost of a partial EMT existing in a "ready-to-go" fashion (63).…”

Section: Receptor Tyrosine Kinases (Rtks)mentioning

confidence: 99%

“…Surprisingly, drug-withdrawal may further enhance the EMT state due to an EGFR-mediated boost of a partial EMT existing in a "ready-to-go" fashion (63). A recent study suggested a role for TGF-β in mediating the RTK switch with accompanying activation of AKT and EMT, hence, rendering cells independent of EGFR signaling (52). An increase in TGF-β during resistance development could create an autocrine loop, linking the kinase switch and EMT.…”

Section: Receptor Tyrosine Kinases (Rtks)mentioning

confidence: 99%

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The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

Jakobsen

Demuth

Sørensen³

et al. 2016

Transl. Lung Cancer Res.

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Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and resistance to lung cancer therapy Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. The 5-year survival remains at 10-15% despite advances in treatment options.Erlotinib, a TKI targeting EGFR, was initially explored as a second-line treatment in NSCLC patients progressing on standard chemotherapy. Survival was prolonged compared to placebo (1). However, erlotinib was soon discovered to be especially efficient in patients with a mutation in the tyrosine kinase domain of EGFR. These patients are nowThe role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer Correspondence to: Anders Lade Nielsen. Department of Biomedicine, Bartholin Building, Aarhus University, DK-8000, Aarhus C, Denmark.Email: aln@biomed.au.dk.Abstract: Inhibition of the epidermal growth factor receptor (EGFR) is an important strategy when treating non-small cell lung cancer (NSCLC) patients. However, intrinsic resistance or development of resistance during the course of treatment constitutes a major challenge. The knowledge on EGFRdirected tyrosine kinase inhibitors (TKIs) and their biological effect keeps increasing. Within the group of patients with EGFR mutations some benefit to a much higher degree than others, and for patients lacking EGFR mutations a subset experience an effect. Up to 70% of patients with EGFR mutations and 10-20% of patients without EGFR mutations initially respond to the EGFR-TKI erlotinib, but there is a severe absence of good prognostic markers. Despite initial effect, all patients acquire resistance to EGFR-TKIs.Multiple mechanisms have implications in resistance development, but much is still to be explored. Epithelial to mesenchymal transition (EMT) is a transcriptionally regulated phenotypic shift rendering cells more invasive and migratory. Within the EMT process lays a need for external or internal stimuli to give rise to changes in central signaling pathways. Expression of mesenchymal markers correlates to a bad prognosis and an inferior response to EGFR-TKIs in NSCLC due to the contribution to a resistant phenotype. A deeper understanding of the role of EMT in NSCLC and especially in EGFR-TKI resistance-development constitute one opportunity to improve the benefit of TKI treatment for the individual patient. Many scientific studies have linked the EMT process to EGFR-TKI resistance in NSCLC and our aim is to review the role of EMT in both intrinsic and acquired resistance to EGFR-TKIs.Keywords: Epidermal growth factor receptor (EGFR); epithelial to mesenchymal transition (EMT); non-small cell lung cancer (NSCLC); tyrosine kinase inhibitor (TKI)

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EMT‐associated microRNAs and their roles in cancer stemness and drug resistance

Pan

Liu

Zhou

et al. 2021

Cancer Communications

219

126

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Epithelial‐to‐mesenchymal transition (EMT) is implicated in a wide array of malignant behaviors of cancers, including proliferation, invasion, and metastasis. Most notably, previou studies have indicated that both cancer stem‐like properties and drug resistance were associated with EMT. Furthermore, microRNAs (miRNAs) play a pivotal role in the regulation of EMT phenotype, as a result, some miRNAs impact cancer stemness and drug resistance. Therefore, understanding the relationship between EMT‐associated miRNAs and cancer stemness/drug resistance is beneficial to both basic research and clinical treatment. In this review, we preliminarily looked into the various roles that the EMT‐associated miRNAs play in the stem‐like nature of malignant cells. Then, we reviewed the interaction between EMT‐associated miRNAs and the drug‐resistant complex signaling pathways of multiple cancers including lung cancer, gastric cancer, gynecologic cancer, breast cancer, liver cancer, colorectal cancer, pancreatic cancer, esophageal cancer, and nasopharyngeal cancer. We finally discussed the relationship between EMT, cancer stemness, and drug resistance, as well as looked forward to the potential applications of miRNA therapy for malignant tumors.

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The TGFβ–miR200–MIG6 Pathway Orchestrates the EMT-Associated Kinase Switch That Induces Resistance to EGFR Inhibitors

Cited by 113 publications

References 41 publications

miR-200c: a versatile watchdog in cancer progression, EMT, and drug resistance

miR-200c: a versatile watchdog in cancer progression, EMT, and drug resistance

The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

EMT‐associated microRNAs and their roles in cancer stemness and drug resistance

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