Notch3-dependent β-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC

Arasada, Rajeswara Rao; Shilo, Konstantin; Yamada, Tadaaki; Zhang, Jianying; Yano, Seiji; Ghanem, Rashelle; Wang, Walter; Takeuchi, Shinji; Fukuda, Koji; Katakami, Nobuyuki; Tomii, Keisuke; Ogushi, Fumitaka; Nishioka, Yasuhiko; Talabere, Tiffany; Misra, Shrilekha; Duan, Wenrui; Fadda, Paolo; Rahman, Mohammad Aminur; Nana‐Sinkam, Patrick; Evans, Jason V.; Amann, Joseph M.; Tchekneva, Elena E.; Dikov, Mikhail M.; Carbone, David P.

doi:10.1038/s41467-018-05626-2

Cited by 66 publications

(53 citation statements)

References 63 publications

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“…Activation of several signaling transducers were associated with persistent drug tolerance to EGFR TKI treatments, including Akt, Notch, and Casein Kinase 1. 49 , 50 , 51 These transducers are not miR-146b-5p targets and may contribute to the survival of PC9/ge-miR-146b-5p cells in high concentration of gefitinib. The phenomenon was reported in previous study.…”

Section: Discussionmentioning

confidence: 99%

miR-146b-5p Enhances the Sensitivity of NSCLC to EGFR Tyrosine Kinase Inhibitors by Regulating the IRAK1/NF-κB Pathway

Liu

Tsai

et al. 2020

Molecular Therapy - Nucleic Acids

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Although patients with non-small cell lung cancer harboring activating mutations in the epidermal growth factor receptor (EGFR) show good clinical response to EGFR tyrosine kinase inhibitors (TKIs), patients eventually develop acquired resistance. Previous studies have shown that several microRNAs (miRNAs) are involved in EGFR TKI resistance. Here, we aimed to investigate whether miR-146b-5p sensitizes the EGFR TKI-resistant lung cancer cells. Clinical analysis showed that miR-146b-5p expression in lung cancer cells isolated from pleural effusions of treatment-naive patients was significantly higher than that after acquiring resistance to EGFR TKI treatment. Ectopic expression of miR-146b-5p in EGFR TKI-resistant cells enhanced EGFR TKI-induced apoptosis. The same results were observed in EGFR-dependent and -independent osimertinib-resistant primary cancer cells (PE3479 and PE2988). Mechanically, miR-146b-5p suppressed nuclear factor κB (NF-κB) activity and NF-κB-related IL-6 and IL-8 production by targeting IRAK1 . A negative correlation was observed between miR-146b-5p and IRAK1 in clinical specimens. In rescue experiments, restoration of IRAK1 expression reversed the effects of miR-146b-5p on EGFR TKI sensitivity and recovered NF-κB-regulated IL-6 and IL-8 production. In conclusion, miR-146b-5p/IRAK1/NF-κB signaling is important in promoting EGFR TKI resistance, and miR-146b-5p may be a useful tool for overcoming EGFR TKI resistance.

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Section: Discussionmentioning

confidence: 99%

miR-146b-5p Enhances the Sensitivity of NSCLC to EGFR Tyrosine Kinase Inhibitors by Regulating the IRAK1/NF-κB Pathway

Liu

Tsai

et al. 2020

Molecular Therapy - Nucleic Acids

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“…Combined inhibition of EGFR and Notch 3 using pan-Notch GSIs was able to reverse the stem-like phenotype [ 158 ]. Subsequent work showed that EGFR TKI activation of Notch 3 in EGFR-mutant lung cancer cells is accompanied by stabilisation and activation of β-catenin [ 159 ].…”

Section: Notch Crosstalk With Other Signalling Pathways and Therapmentioning

confidence: 99%

Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives

Moore

Annett

McClements

et al. 2020

Cells

103

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Evolutionarily conserved Notch plays a critical role in embryonic development and cellular self-renewal. It has both tumour suppressor and oncogenic activity, the latter of which is widely described. Notch-activating mutations are associated with haematological malignancies and several solid tumours including breast, lung and adenoid cystic carcinoma. Moreover, upregulation of Notch receptors and ligands and aberrant Notch signalling is frequently observed in cancer. It is involved in cancer hallmarks including proliferation, survival, migration, angiogenesis, cancer stem cell renewal, metastasis and drug resistance. It is a key component of cell-to-cell interactions between cancer cells and cells of the tumour microenvironment, such as endothelial cells, immune cells and fibroblasts. Notch displays diverse crosstalk with many other oncogenic signalling pathways, and may drive acquired resistance to targeted therapies as well as resistance to standard chemo/radiation therapy. The past 10 years have seen the emergence of different classes of drugs therapeutically targeting Notch including receptor/ligand antibodies, gamma secretase inhibitors (GSI) and most recently, the development of Notch transcription complex inhibitors. It is an exciting time for Notch research with over 70 cancer clinical trials registered and the first-ever Phase III trial of a Notch GSI, nirogacestat, currently at the recruitment stage.

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“…Interestingly, in this latter phenomenon, the observed tumor driving induction effect of Notch3 seems to be dependent on direct physical (biochemical) interaction with EGFR and Notch3 tyrosine phosphorylation modification, although the exact residue(s) undergoing this posttranslational regulation has not yet been identified [101]. Remarkably, it should be noted that while Notch3 mediates EGFR regulation of the Wnt/β-catenin pathway in EGFR mutant NSCLC, a dominant negative form of Mastermind-like (dn-MAML) is ineffective in preventing the expansion of ALDH + CSCs in these tumors, indicating that Notch3 action is likely due to non-canonical activity [102]. Notably, in Kras-mutant ACL tumor cells upregulation of Notch3 expression has also been observed in a signaling pathways' interplay requiring PKCι-mediated ELF3 phosphorylation and the subsequent Notch3 promoter occupancy and transcriptional activation that, furthermore, leads to enhanced CSC phenotype [103].…”

Section: Notch and Nsclcmentioning

confidence: 99%

Notch Transduction in Non-Small Cell Lung Cancer

Sharif

Shaji

Chammaa

et al. 2020

IJMS

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The evolutionarily-conserved Notch signaling pathway plays critical roles in cell communication, function and homeostasis equilibrium. The pathway serves as a cell-to-cell juxtaposed molecular transducer and is crucial in a number of cell processes including cell fate specification, asymmetric cell division and lateral inhibition. Notch also plays critical roles in organismal development, homeostasis, and regeneration, including somitogenesis, left-right asymmetry, neurogenesis, tissue repair, self-renewal and stemness, and its dysregulation has causative roles in a number of congenital and acquired pathologies, including cancer. In the lung, Notch activity is necessary for cell fate specification and expansion, and its aberrant activity is markedly linked to various defects in club cell formation, alveologenesis, and non-small cell lung cancer (NSCLC) development. In this review, we focus on the role this intercellular signaling device plays during lung development and on its functional relevance in proximo-distal cell fate specification, branching morphogenesis, and alveolar cell determination and maturation, then revise its involvement in NSCLC formation, progression and treatment refractoriness, particularly in the context of various mutational statuses associated with NSCLC, and, lastly, conclude by providing a succinct outlook of the therapeutic perspectives of Notch targeting in NSCLC therapy, including an overview on prospective synthetic lethality approaches.

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Notch3-dependent β-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC

Cited by 66 publications

References 63 publications

miR-146b-5p Enhances the Sensitivity of NSCLC to EGFR Tyrosine Kinase Inhibitors by Regulating the IRAK1/NF-κB Pathway

miR-146b-5p Enhances the Sensitivity of NSCLC to EGFR Tyrosine Kinase Inhibitors by Regulating the IRAK1/NF-κB Pathway

Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives

Notch Transduction in Non-Small Cell Lung Cancer

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