Cause-and-Effect relationship between FGFR1 expression and epithelial-mesenchymal transition in EGFR-mutated non-small cell lung cancer cells

Vad-Nielsen, Johan; Gammelgaard, Kristine Raaby; Daugaard, Tina Fuglsang; Nielsen, Anders Lade

doi:10.1016/j.lungcan.2019.04.023

Cited by 22 publications

(20 citation statements)

References 55 publications

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“…Increased FGFR1 expression and signaling have previously been associated with EMT (8,9,19). Here, we observed a substantial increase in FGFR1 expression in all resistant cell lines (Figure 3A,B) that occurred simultaneously with increase in expression of vimentin and ZEB1 (Figure 3C, Figure 2D, Figure S4).…”

Section: Fgfr1 Is Involved In Met-tki Resistancesupporting

confidence: 70%

“…This suggests that FGFR1 bypass signaling is a preferred mechanism to obtain an immediate survival benefit upon TKI-mediated inhibition of the primarily used RTK signaling pathways. Increased FGFR1 expression has also been associated with EMT markers in clinical samples, but further research is needed to determine the significance of FGFR1 in clinical development of TKI resistance (19,27). Furthermore, four out of the six MET-TKI resistant cell lines showed increased sensitivity to treatment with the pan-FGFR inhibitor AZD4547 compared to the parental cells.…”

Section: Fgfr1 Is Involved In Met-tki Resistancementioning

confidence: 99%

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Epithelial-to-mesenchymal transition is a resistance mechanism to sequential MET-TKI treatment of MET-amplified EGFR-TKI resistant non-small cell lung cancer cells

Clement¹,

Gammelgaard²,

Nielsen³

et al. 2020

Transl Lung Cancer Res

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Background: Tyrosine kinase inhibitor (TKI) resistance is a major obstacle in treatment of non-small cell lung cancer (NSCLC). MET amplification drives resistance to EGFR-TKIs in 5-20% of initially sensitive EGFR-mutated NSCLC patients, and combined treatment with EGFR-TKIs and MET-TKIs can overcome this resistance. Yet, inevitably MET-TKI resistance will also occur. Hence, knowledge on development of this sequential resistance is important for identifying the proper next step in treatment.Methods: To investigate sequential resistance to MET-TKI treatment, we established a two-step TKI resistance model in EGFR-mutated HCC827 cells with MET amplification-mediated erlotinib resistance.These cells were subsequently treated with increasing doses of the MET-TKIs capmatinib or crizotinib in combination with erlotinib to establish resistance.Results: In all the MET-TKI resistant cell lines, we systematically observed epithelial-to-mesenchymal transition (EMT) evident by decreased expression of E-cadherin and increased expression of vimentin and ZEB1. Furthermore, FGFR1 expression was increased in all MET-TKI resistant cell lines and four out of the six resistant cell lines had increased sensitivity to FGFR inhibition, indicating FGFR1-mediated bypass signaling.Conclusions: EMT is common in the development of sequential EGFR-TKI and MET-TKI resistance in NSCLC cells. Our findings contribute to the evidence of EMT as a common TKI resistance mechanism.

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Section: Fgfr1 Is Involved In Met-tki Resistancesupporting

confidence: 70%

Section: Fgfr1 Is Involved In Met-tki Resistancementioning

confidence: 99%

Epithelial-to-mesenchymal transition is a resistance mechanism to sequential MET-TKI treatment of MET-amplified EGFR-TKI resistant non-small cell lung cancer cells

Clement¹,

Gammelgaard²,

Nielsen³

et al. 2020

Transl Lung Cancer Res

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“…Considering the possible resistance genes revealed in this study, fibroblast growth factor receptor 1 (FGFR1), C-C chemokine receptor type 2 (CCR2), and serum/glucocorticoid regulated kinase 1 (SGK1) were overexpressed in KMS-20 cells. FGFR1 contributes to tyrosine kinase inhibitor resistance and chemoresistance in lung, breast, and urothelial cancers [48][49][50]. The activation of CCR2 is involved in resistance to regorafenib, a multikinase inhibitor, and cabazitaxel in colon and prostate cancer cells [33,34].…”

Section: Discussionmentioning

confidence: 99%

Activation of Serum/Glucocorticoid Regulated Kinase 1/Nuclear Factor-κB Pathway Are Correlated with Low Sensitivity to Bortezomib and Ixazomib in Resistant Multiple Myeloma Cells

et al. 2021

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Multiple myeloma (MM) is an incurable malignancy often associated with primary and acquired resistance to therapeutic agents, such as proteasome inhibitors. However, the mechanisms underlying the proteasome inhibitor resistance are poorly understood. Here, we elucidate the mechanism of primary resistance to bortezomib and ixazomib in the MM cell lines, KMS-20, KMS-26, and KMS-28BM. We find that low bortezomib and ixazomib concentrations induce cell death in KMS-26 and KMS-28BM cells. However, high bortezomib and ixazomib concentrations induce cell death only in KMS-20 cells. During Gene Expression Omnibus analysis, KMS-20 cells exhibit high levels of expression of various genes, including anti-phospho-fibroblast growth factor receptor 1 (FGFR1), chemokine receptor type (CCR2), and serum and glucocorticoid regulated kinase (SGK)1. The SGK1 inhibitor enhances the cytotoxic effects of bortezomib and ixazomib; however, FGFR1 and CCR2 inhibitors do not show such effect in KMS-20 cells. Moreover, SGK1 activation induces the phosphorylation of NF-κB p65, and an NF-κB inhibitor enhances the sensitivity of KMS-20 cells to bortezomib and ixazomib. Additionally, high levels of expression of SGK1 and NF-κB p65 is associated with a low sensitivity to bortezomib and a poor prognosis in MM patients. These results indicate that the activation of the SGK1/NF-κB pathway correlates with a low sensitivity to bortezomib and ixazomib, and a combination of bortezomib and ixazomib with an SGK1 or NF-κB inhibitor may be involved in the treatment of MM via activation of the SGK1/NF-κB pathway.

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“…Indeed, it appears that in the context of acquired resistance to EGFR inhibitors, FGFR activation is almost inevitably accompanied by gain of mesenchymal features (by phenotypic transformation toward more mesenchymal phenotype) (Jakobsen et al, 2017). To address causative relationship between FGFR1 activation and onset of EMT, either FGFR1 or ZEB1 were overexpressed in EGFR-mutant, treatment-naïve cells (Vad-Nielsen et al, 2019). Cells expressing high levels of ZEB1 underwent EMT and upregulated FGFR1 expression.…”

Section: The Role Of Emt In Acquired Resistance To Egfr Tkis Emt Co-omentioning

confidence: 99%

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

et al. 2020

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Somatic alterations in the epidermal growth factor receptor gene (EGFR) result in aberrant activation of kinase signaling and occur in ∼15% of non-small cell lung cancers (NSCLC). Patients diagnosed with EGFR-mutant NSCLC have good initial clinical response to EGFR tyrosine kinase inhibitors (EGFR TKIs), yet tumor recurrence is common and quick to develop. Mechanisms of acquired resistance to EGFR TKIs have been studied extensively over the past decade. Great progress has been made in understanding two major routes of therapeutic failure: additional genomic alterations in the EGFR gene and activation of alternative kinase signaling (so-called "bypass activation"). Several pharmacological agents aimed at overcoming these modes of EGFR TKI resistance are FDA-approved or under clinical development. Phenotypic transformation, a less common and less well understood mechanism of EGFR TKI resistance is yet to be addressed in the clinic. In the context of acquired EGFR TKI resistance, phenotypic transformation encompasses epithelial to mesenchymal transition (EMT), transformation of adenocarcinoma of the lung (LUAD) to squamous cell carcinoma (SCC) or small cell lung cancer (SCLC). SCLC transformation, or neuroendocrine differentiation, has been linked to inactivation of TP53 and RB1 signaling. However, the exact mechanism that permits lineage switching needs further investigation. Recent reports indicate that LUAD and SCLC have a common cell of origin, and that trans-differentiation occurs under the right conditions. Options for therapeutic targeting of EGFR-mutant SCLC are limited currently to conventional genotoxic chemotherapy. Similarly, the basis of EMT-associated resistance is not clear. EMT is a complex process that can be characterized by a spectrum of intermediate states with diverse expression of epithelial and mesenchymal factors. In the context of acquired resistance to EGFR TKIs, EMT frequently co-occurs with bypass activation, making it challenging to determine the exact contribution of EMT to therapeutic failure. Reversibility of EMT-associated resistance points toward its epigenetic origin, with additional adjustments, such as genetic alterations and bypass activation, occurring later during disease progression. This review will discuss the mechanistic basis for EGFR TKI resistance linked to phenotypic transformation, as well as challenges and opportunities in addressing this type of targeted therapy resistance in EGFR-mutant NSCLC.

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Cause-and-Effect relationship between FGFR1 expression and epithelial-mesenchymal transition in EGFR-mutated non-small cell lung cancer cells

Cited by 22 publications

References 55 publications

Epithelial-to-mesenchymal transition is a resistance mechanism to sequential MET-TKI treatment of MET-amplified EGFR-TKI resistant non-small cell lung cancer cells

Epithelial-to-mesenchymal transition is a resistance mechanism to sequential MET-TKI treatment of MET-amplified EGFR-TKI resistant non-small cell lung cancer cells

Activation of Serum/Glucocorticoid Regulated Kinase 1/Nuclear Factor-κB Pathway Are Correlated with Low Sensitivity to Bortezomib and Ixazomib in Resistant Multiple Myeloma Cells

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

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