Gefitinib Inhibits Invasive Phenotype and Epithelial-Mesenchymal Transition in Drug-Resistant NSCLC Cells with MET Amplification

Monica, Silvia La; Caffarra, Cristina; Saccani, Francesca; Galvani, Elena; Galetti, Maricla; Fumarola, Claudia; Bonelli, Mara; Cavazzoni, Andrea; Cretella, Daniele; Sirangelo, Rita; Gatti, Rita; Tiseo, Marcello; Ardizzoni, Andrea; Giovannetti, Elisa; Petronini, Pier Giorgio; Alfieri, Roberta

doi:10.1371/journal.pone.0078656

Cited by 38 publications

(32 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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). 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).…”

Section: Receptor Tyrosine Kinases (Rtks)mentioning

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.

View full text Add to dashboard Cite

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)

show abstract

Section: Receptor Tyrosine Kinases (Rtks)mentioning

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.

View full text Add to dashboard Cite

show abstract

“…S3A). Next, a Cre-inducible allele of the MET receptor tyrosine kinase, which is associated with EMT and therapy resistance (18,19), and expressed at high levels in breast cancer (20)(21)(22), was introduced in KB1P-Col1a1 ESC clone A2.1 to produce K14cre;Brca1 F/F ; Trp53 F/F ;Col1a1 inv-CAG-Met-Luc (KB1P-MET) ESCs (Fig. S3B).…”

Section: Met Accelerates Mammary Tumor Development In Kb1p Chimericmentioning

confidence: 99%

Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer

Henneman

Miltenburg

Michalak

et al. 2015

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

107

View full text Add to dashboard Cite

Metaplastic breast carcinoma (MBC) is a rare histological breast cancer subtype characterized by mesenchymal elements and poor clinical outcome. A large fraction of MBCs harbor defects in breast cancer 1 (BRCA1). As BRCA1 deficiency sensitizes tumors to DNA cross-linking agents and poly(ADP-ribose) polymerase (PARP) inhibitors, we sought to investigate the response of BRCA1-deficient MBCs to the PARP inhibitor olaparib. To this end, we established a genetically engineered mouse model (GEMM) for BRCA1-deficient MBC by introducing the MET proto-oncogene into a BRCA1-associated breast cancer model, using our novel female GEMM ES cell (ESC) pipeline. In contrast to carcinomas, BRCA1-deficient mouse carcinosarcomas resembling MBC show intrinsic resistance to olaparib caused by increased P-glycoprotein (Pgp) drug efflux transporter expression. Indeed, resistance could be circumvented by using another PARP inhibitor, AZD2461, which is a poor Pgp substrate. These preclinical findings suggest that patients with BRCA1-associated MBC may show poor response to olaparib and illustrate the value of GEMM-ESC models of human cancer for evaluation of novel therapeutics. resistance | mouse model | breast cancer | BRCA1 | PARP P oly(ADP-ribose) polymerase (PARP) inhibition provides a promising therapeutic strategy for targeting homologous recombination (HR)-deficient tumors, such as breast cancer 1 (BRCA1)-mutated cancers (1). Indeed, clinical phase I and phase II trials have shown potent anticancer activity of small molecule inhibitors of PARP, such as olaparib, in patients with BRCA1-associated breast cancer (2, 3). However, it remains to be established whether different breast cancer subtypes in BRCA1 mutation carriers respond equally to PARP inhibition. Reduced sensitivity of breast cancers to anticancer drugs has frequently been associated with an epithelial-to-mesenchymal transition (EMT) (4-7). Metaplastic breast carcinomas (MBCs) are a subset of triple-negative breast cancers (TNBCs) characterized by a claudin-low and EMT-like phenotype (8) and a poor prognosis compared with other TNBCs (9). More than 60% of MBCs have BRCA1 promoter methylation, raising the question whether these tumors can be effectively targeted by using PARP inhibitors (10). To address this issue in an experimentally controlled setting, we set out to generate a genetically engineered mouse model (GEMM) of BRCA1-deficient MBC by inducing EMT via MET overexpression in a previously established GEMM of BRCA1-mutated breast cancer. We report that EMT is associated with olaparib resistance and can be effectively bypassed by administration of AZD2461, a PARP inhibitor with low affinity for the P-glycoprotein (Pgp) drug efflux transporter. Results Development of a GEMM-ESC Strategy for Mouse Mammary TumorModels. GEMMs have the potential to capture the cell-intrinsic and cell-extrinsic factors that drive de novo tumor formation, making them exceptionally valuable for cancer research (11). To speed up the development of novel multiallele GEMMs of human cancer, we...

show abstract

“…Clinical studies demonstrated that certain EGF receptor-mutated patients could benefit from a second-line therapy including gefitinib and erlotinib through reversal of drug resistance. The data showed that gefitinib and erlotinib could reduce cell migration and invasion and prevent EMT from developing [59]. These phenomena offer an interesting treatment approach if these substances are well tolerated and able to be combined with conventional or targeted therapies where there is evidence of EMT-mediated resistance.…”

Section: Therapeutic Strategy For Drug Resistance Via Emtmentioning

confidence: 99%

Epithelial-Mesenchymal Transition and Drug Resistance: Role, Molecular Mechanisms, and Therapeutic Strategies

Sui

Zhu²,

Deng

et al. 2014

Oncol Res Treat

View full text Add to dashboard Cite

SummaryChemotherapy is an important therapeutic option for most cancer patients; however, one major obstacle is the occurrence of drug resistance which usually leads to failure of the chemotherapy. Emerging evidence suggests that there are intricate links between epithelial-mesenchymal transition (EMT)-type cells and drug resistance in tumors. The process of drug resistance can be regulated by a diverse array of cytokines and growth factors, higher apoptotic threshold, aerobic glycolysis, regions of hypoxia, and elevated activity of drug efflux transporters. Moreover, recent reports have indicated that the emergence of drug resistance may occur as a result of EMT. In this regard, most drug-resistant cancers contain a subpopulation of cells with stem-like and mesenchymal features that are resistant to chemotherapy. In this review, we will explain potential mechanisms for the association between EMT induction and the emergence of drug resistance, and discuss new approaches and drugs for the clinical management of drug-resistant cancer induced by EMT.

show abstract

Gefitinib Inhibits Invasive Phenotype and Epithelial-Mesenchymal Transition in Drug-Resistant NSCLC Cells with MET Amplification

Cited by 38 publications

References 49 publications

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

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

Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer

Epithelial-Mesenchymal Transition and Drug Resistance: Role, Molecular Mechanisms, and Therapeutic Strategies

Contact Info

Product

Resources

About