EGFR Blockade Enriches for Lung Cancer Stem–like Cells through Notch3-Dependent Signaling

Arasada, Rajeswara Rao; Amann, Joseph M.; Rahman, Mohammad Aminur; Huppert, Stacey S.; Carbone, David P.

doi:10.1158/0008-5472.can-13-3724

Cited by 111 publications

(111 citation statements)

References 47 publications

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“…49 Pending the full publication of this trial and the results of similar studies, the continuation of an EGFR TKI in combination with chemotherapy should only be addressed in the setting of a clinical trial.These results are similar with those derived from four older phase 3 trials in molecularly unselected patients with NSCLC where the upfront co-administration of erlotinib or gefitinib with chemotherapy did not improve the clinical outcome compared to chemotherapy alone [50][51][52][53]. Recently, in the FASTACT-2 trial, the doublet of a platinum salt and gemcitabine was combined with intercalated administration of erlotinib (150 mg qd on days[15][16][17][18][19][20][21][22][23][24][25][26][27][28] or placebo. Among the 451 enrolled patients, 97 harbored an activating EGFR mutation while EGFR status was unknown in 210 patients.…”

supporting

confidence: 80%

“…24,25 Moreover, it has been recently shown that blocking the EGFR, in mutant EGFR NSCLC cell lines with erlotinib leads to activation of Notch signaling, thus promoting stem-like cell characteristics which likely further contribute to the emergence of resistance and disease progression. 26 Phenotypic transformation: A rare but well documented mechanism of resistance to EGFR inhibition is the transformation to small cell lung cancer (SCLC), mediated by the activation of the AXL kinase. 27 The inhibition of AXL might be an ideal alternative approach in an attempt to reverse resistance and to restore sensitivity to EGFR TKIs.…”

Section: Egfr Alterationsmentioning

confidence: 99%

See 1 more Smart Citation

Current and Future Approaches in the Management of Non–Small-Cell Lung Cancer Patients With Resistance to EGFR TKIs

Matikas¹,

Mistriotis²,

Georgoulias³

et al. 2015

Clinical Lung Cancer

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supporting

confidence: 80%

Section: Egfr Alterationsmentioning

confidence: 99%

Current and Future Approaches in the Management of Non–Small-Cell Lung Cancer Patients With Resistance to EGFR TKIs

Matikas¹,

Mistriotis²,

Georgoulias³

et al. 2015

Clinical Lung Cancer

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“…These features make the KP murine model a useful tool with which to evaluate factors that underlie NSCLC metastasis. Among the pathways activated in metastasis, a significant number are associated with tumor-initiating progenitor cell populations (6)(7)(8)(9)(10)(11)(12). In this study, using cell lines with high or low metastatic potential derived from multiple independent tumors arising in KP mice (13), we evaluated a set of genes associated with progenitor cell identity as candidate regulators of the invasive and metastatic properties of NSCLC tumors.…”

Section: R175hδgmentioning

confidence: 99%

Musashi-2 (MSI2) supports TGF-β signaling and inhibits claudins to promote non-small cell lung cancer (NSCLC) metastasis

Kudinov

Deneka

Nikonova

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

130

140

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Non-small cell lung cancer (NSCLC) has a 5-y survival rate of ∼16%, with most deaths associated with uncontrolled metastasis. We screened for stem cell identity-related genes preferentially expressed in a panel of cell lines with high versus low metastatic potential, derived from NSCLC tumors of Kras LA1/+ ;P53 R172HΔG/+ (KP) mice. The Musashi-2 (MSI2) protein, a regulator of mRNA translation, was consistently elevated in metastasis-competent cell lines. MSI2 was overexpressed in 123 human NSCLC tumor specimens versus normal lung, whereas higher expression was associated with disease progression in an independent set of matched normal/primary tumor/lymph node specimens. Depletion of MSI2 in multiple independent metastatic murine and human NSCLC cell lines reduced invasion and metastatic potential, independent of an effect on proliferation. MSI2 depletion significantly induced expression of proteins associated with epithelial identity, including tight junction proteins [claudin 3 (CLDN3), claudin 5 (CLDN5), and claudin 7 (CLDN7)] and down-regulated direct translational targets associated with epithelial-mesenchymal transition, including the TGF-β receptor 1 (TGFβR1), the small mothers against decapentaplegic homolog 3 (SMAD3), and the zinc finger proteins SNAI1 (SNAIL) and SNAI2 (SLUG). Overexpression of TGFβRI reversed the loss of invasion associated with MSI2 depletion, whereas overexpression of CLDN7 inhibited MSI2-dependent invasion. Unexpectedly, MSI2 depletion reduced E-cadherin expression, reflecting a mixed epithelialmesenchymal phenotype. Based on this work, we propose that MSI2 provides essential support for TGFβR1/SMAD3 signaling and contributes to invasive adenocarcinoma of the lung and may serve as a predictive biomarker of NSCLC aggressiveness.on-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths in the world (1). Approximately 7% of individuals born in the United States in 2013 will ultimately be diagnosed with lung cancer, and 160,000 die from this disease each year (1). The 5-y survival rate for lung cancer is around 16% of diagnosed cases (2). Much of the lethality of lung cancer is due to frequent diagnosis of the malignancy at the metastatic stage, when fundamental changes in tumor biology cause the disease to be refractory to many treatments. A better understanding of the biological processes that promote NSCLC metastasis promises to further improve clinical care of the patients. Kras LA1/+ ;P53 R172HΔG/+ (KP) mice provide a useful and wellvalidated model for the study of NSCLC metastasis. These mice combine a mutant p53 allele (p53 R175HΔG) with an activating KrasG12D allele (Kras LA1 ) (3), leading to development of adenocarcinomas resembling human NSCLC, which are often characterized by mutation of KRAS (∼30%) (4) and loss of TP53 (∼60%) (5). Many of the KP tumors metastasize to sites commonly seen in NSCLC patients (3). These features make the KP murine model a useful tool with which to evaluate factors that underlie NSCLC metastasis. Among the pathways activated...

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“…Several links between EMT-induction and EGFR-TKI treatment exists (Figure 2). In the instance of Notchinduced EMT, Notch is activated during EGFR-TKI treatment as EGFR signaling normally has a repressive effect on this pathway (48).…”

Section: Molecular Mechanisms For Emt Induction Related To Egfr-tki Rmentioning

confidence: 99%

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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EGFR Blockade Enriches for Lung Cancer Stem–like Cells through Notch3-Dependent Signaling

Cited by 111 publications

References 47 publications

Current and Future Approaches in the Management of Non–Small-Cell Lung Cancer Patients With Resistance to EGFR TKIs

Current and Future Approaches in the Management of Non–Small-Cell Lung Cancer Patients With Resistance to EGFR TKIs

Musashi-2 (MSI2) supports TGF-β signaling and inhibits claudins to promote non-small cell lung cancer (NSCLC) metastasis

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

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