Notch inhibition overcomes resistance to tyrosine kinase inhibitors in EGFR-driven lung adenocarcinoma

Mur, Emilie Bousquet; Bernardo, Sara; Papon, Laura; Mancini, Maicol; Fabbrizio, Eric; Goussard, Marion; Ferrer, Irene; Giry, Anais; Quantin, Xavier; Pujol, Jean-Louis; Calvayrac, Olivier; Moll, Herwig P.; Glasson, Yaël; Pirot, Nelly; Turtoï, Andrei; Cañamero, Marta; Wong, Kwok-Kin; Yarden, Yosef; Casanova, Emilio; Soria, Jean‐Charles; Colinge, Jacques; Siebel, Christian W.; Favre, Gilles; Paz‐Ares, Luis; Maraver, Antonio

doi:10.1172/jci126896

Cited by 35 publications

(35 citation statements)

References 52 publications

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“…54 EGFR tyrosine kinase inhibitor-resistant lung cancer was also found to be responsive to the combined treatment of Notch inhibitors with EGFR inhibitors, gefitinib, or osimertinib. 55 These studies further strengthen the concept of dual targeting of EGFR and Notch signaling in blocking tumor growth. It remains unclear how EGFR inhibition might affect Notch signaling in MEC, as we observed a reduced level of HES1 expression in MEC with the treatment of EGFRi.…”

Section: Discussionmentioning

confidence: 62%

Targeting Notch and EGFR signaling in human mucoepidermoid carcinoma

Chen

Zhou

et al. 2021

Sig Transduct Target Ther

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Mucoepidermoid carcinoma (MEC) is the most common type of salivary gland cancers and patients with advanced, metastatic, and recurrent MECs have limited therapeutic options and poor treatment outcomes. MEC is commonly associated with a chromosomal translocation t(11;19) (q14-21;p12-13) that encodes the CRTC1-MAML2 oncogenic fusion. The CRTC1-MAML2 fusion is required for MEC growth in part through inducing autocrine AREG-EGFR signaling. Growing evidence suggests that MEC malignancy is maintained by cancer stem-like cells. In this study, we aimed to determine critical signaling for maintaining MEC stem-like cells and the effect of combined targeting of stem cell signaling and CRTC1-MAML2-induced EGFR signaling on blocking MEC growth. First, we evaluated the significance of Notch signaling in regulating MEC stem-like cells. Aberrantly activated Notch signaling was detected in human fusion-positive MEC cells. The inhibition of Notch signaling with genetic or pharmacological inhibitors reduced oncosphere formation and ALDH-bright population in vitro and blocked the growth of MEC xenografts in vivo. Next, we investigated the effect of co-targeting Notch signaling and EGFR signaling, and observed enhanced inhibition on MEC growth in vivo. Collectively, this study identified a critical role of Notch signaling in maintaining MEC stem-like cells and tumor growth, and revealed a novel approach of co-targeting Notch and EGFR signaling as a potential effective anti-MEC treatment.

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Section: Discussionmentioning

confidence: 62%

Targeting Notch and EGFR signaling in human mucoepidermoid carcinoma

Chen

Zhou

et al. 2021

Sig Transduct Target Ther

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“…Given that Notch signalling is frequently overexpressed in cancer and has a key role in a diverse range of cellular processes, it is not surprising that Notch displays diverse crosstalk with many other oncogenic signalling pathways such as developmental signals (Hedgehog and WNT), growth factors, steroids, oncogenic kinases and transcription factors. Increasing evidence suggests Notch signalling is associated with treatment resistance to molecular therapies targeting other oncogenic pathways including HER2 (e.g., trastuzumab), EGFR (e.g., gefitinib), proangiogenic VEGF signalling (e.g., brivanib and sorafenib) and steroid signalling (e.g., tamoxifen and enzalutamide) [ 144 , 145 , 146 , 147 , 148 , 149 , 150 ] or with resistance to cytotoxic chemotherapeutic agents and radiation treatment [ 151 , 152 ]. In recent years, dual or multitargeted therapy approaches have become an attractive treatment strategy to combat resistance.…”

Section: Notch Crosstalk With Other Signalling Pathways and Therapmentioning

confidence: 99%

“…While most EGFR-mutant lung cancer patients respond well to begin with, the development of resistance is inevitable. In 60% of cases, this is due to further acquisition of ”gate-keeper” mutations in EGFR, namely T790M [ 145 ]. Osimertinib, a T790M-specific TKI, has been FDA approved for the treatment of metastatic NSCLC harbouring EGFR T790M mutations, whose disease has progressed on or after EGFR TKI therapy [ 155 ].…”

Section: Notch Crosstalk With Other Signalling Pathways and Therapmentioning

confidence: 99%

“…Beyond lung adenocarcinoma, Notch 3-specific depletion, via siRNA transfection, has been shown to sensitise TNBC cells to gefitinib treatment [ 160 ]. Recent work has shown that NSCLC PDX models harbouring secondary EGFR “gate-keeper” mutations (e.g., EGFRT790M/L858R) that drive resistance to gefitinib and osimertinib can be resensitised to these drugs by including a Notch inhibitor as part of the treatment regimen [ 145 ]. In these PDX models, as expected, EGFR TKIs had no effect on tumour growth, whereas GSI dibenzazepine (DBZ) monotherapy inhibited tumour growth, and dual TKI/GSI treatment completely blocked tumour growth.…”

Section: Notch Crosstalk With Other Signalling Pathways and Therapmentioning

confidence: 99%

“…Clinically relevant GSI, nirogacestat, showed similar activity in combination with gefitinib in an EGFR T790M lung adenocarcinoma cell line xenograft model, providing further rationale for this combined therapeutic strategy in patients with EGFR “gate-keeper” mutations [ 145 ]. Another clinical GSI, RO4929097, in combination with erlotinib was investigated in NSCLC patients in a Phase I/II trial (NCT01193881; Table 1 ).…”

Section: Notch Crosstalk With Other Signalling Pathways and Therapmentioning

confidence: 99%

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

Moore

Annett

McClements

et al. 2020

Cells

108

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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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Histone lysine methyltransferase SETDB2 suppresses NRF2 to restrict tumor progression and modulates chemotherapy sensitivity in lung adenocarcinoma

Yuan

et al. 2022

Cancer Medicine

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Objective Aberrant epigenetic remodeling represents a molecular hallmark in lung adenocarcinoma (LUAD). We aim to investigate the biological roles of SETDB2 and its underlying associations with oxidative stress, providing therapeutic targets for individualized treatment of LUAD. Methods Differential analysis was conducted via Limma package, and Kaplan–Meier analysis was performed with survival package. CCK‐8, cell proliferation assay, transwell assay, and in vivo assays were conducted to assess the function of SETDB2. Western blot assay, RT‐qPCR, and immunohistochemistry (IHC) were conducted to assess the expression levels of SETDB2/NRF2. Chromatin immunoprecipitation (ChIP) assay and ChIP‐qPCR were conducted to assess the epigenetic roles of SETDB2. Results We found that SETDB2 expression is decreased in tumor samples versus normal tissues in TCGA‐LUAD cohort, LUAD‐EAS cohort, GSE72094 dataset, and independent Soochow‐LUAD dataset. Patients with low SETDB2 levels had a worse prognosis relative to those with high SETDB2. SETDB2 inhibition could significantly promote cell growth, migration ability, and stemness maintenance. Gene set enrichment analysis (GSEA) suggested that SETDB2 correlated with oxidative stress crosstalk and regulated NRF2 mRNA levels. ChIP assay suggested that SETDB2 mainly recruited the H3K9me3 enrichment at the NRF2 promoter region to suppress the mRNA levels of NRF2. Downregulated SETDB2 could activate NRF2 transcription and expression, thereby promoting its downstream targets, like NQO1, FTH1, and ME1. Functional experiments demonstrated that low SETDB2 allowed NRF2 to drive malignant processes of LUAD. SETDB2 overexpression attenuated the ability of NRF2 signaling to neutralize cellular reactive oxygen species (ROS) levels, leading to enhanced cell apoptosis. Overexpressed SETDB2 could inhibit tumor progression in vivo and further render LUAD cells sensitive to chemotherapy. Conclusions In conclusion, these findings uncovered the suppressive role of SETDB2 in LUAD. SETDB2 negatively regulates NRF2 signaling to modulate tumor progression, which creates a therapeutic vulnerability in LUAD.

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Notch inhibition overcomes resistance to tyrosine kinase inhibitors in EGFR-driven lung adenocarcinoma

Cited by 35 publications

References 52 publications

Targeting Notch and EGFR signaling in human mucoepidermoid carcinoma

Targeting Notch and EGFR signaling in human mucoepidermoid carcinoma

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

Histone lysine methyltransferase SETDB2 suppresses NRF2 to restrict tumor progression and modulates chemotherapy sensitivity in lung adenocarcinoma

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