Search results for "Gefitinib"

MET-EGFR dimerization in lung adenocarcinoma is dependent on EGFR mtations and altered by MET kinase inhibition

2017

Advanced lung cancer has poor survival with few therapies. EGFR tyrosine kinase inhibitors (TKIs) have high response rates in patients with activating EGFR mutations, but acquired resistance is inevitable. Acquisition of the EGFR T790M mutation causes over 50% of resistance; MET amplification is also common. Preclinical data suggest synergy between MET and EGFR inhibitors. We hypothesized that EGFR-MET dimerization determines response to MET inhibition, depending on EGFR mutation status, independently of MET copy number. We tested this hypothesis by generating isogenic cell lines from NCI-H1975 cells, which co-express L858R and T790M EGFR mutations, namely H1975L858R/T790M (EGFR TKI resista…

Integrating Liquid Biopsy and Radiomics to Monitor Clonal Heterogeneity of EGFR-Positive Non-Small Cell Lung Cancer

2020

BackgroundEGFR-positive Non-small Cell Lung Cancer (NSCLC) is a dynamic entity and tumor progression and resistance to tyrosine kinase inhibitors (TKIs) arise from the accumulation, over time and across different disease sites, of subclonal genetic mutations. For instance, the occurrence of EGFR T790M is associated with resistance to gefitinib, erlotinib, and afatinib, while EGFR C797S causes osimertinib to lose activity. Sensitive technologies as radiomics and liquid biopsy have great potential to monitor tumor heterogeneity since they are both minimally invasive, easy to perform, and can be repeated over patient’s follow-up, enabling the extraction of valuable information. Yet, to date, t…

Molecular Characterization of a Long-Term Survivor Double Metastatic Non-Small Cell Lung Cancer and Pancreatic Ductal Adenocarcinoma Treated with Gef…

2019

The management of multiple primary cancers, an event not so infrequent in oncology practice, is a critical issue due to the lack of literature. In this study, we reported the case of a patient with non-small cell metastatic lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) who received gefitinib in combination with gemcitabine plus nab-paclitaxel and with mFOLFOX6 in first and second line, respectively. It achieved a progression-free survival and a28-months overall survival (OS) for NSCLC and PFS-1 and OS of 20 and 13 months, respectively for PDAC. Moreover, the combination of gefitinib and chemotherapy treatmentsshowed a good safety profile. Given the insignificant frequency …

EGFR inhibition in NSCLC: New findings…. and opened questions?

2017

The targeted inhibition of epidermal growth factor receptor (EGFR) has represented a milestone in the treatment of lung cancer. Several studies convincingly and consistently demonstrated a significant superiority of EGFR-TKIs over standard platinum-chemotherapy in EGFR-mutated NSCLC patients, leading to the sequential approval of gefitinib, erlotinib and afatinib as new standard first-line clinical treatment. To date we are witnessing a second revolution in the management of EGFR-positive NSCLC thanks to the development of new treatment strategies aiming to overcome acquired resistance to TKIs and ultimately improve patients’ outcomes. In this review we summarize the most important recent f…

Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides

2012

Irreversible epidermal growth factor receptor (EGFR) inhibitors contain a reactive warhead which covalently interacts with a conserved cysteine residue in the kinase domain. The acrylamide fragment, a commonly employed warhead, effectively alkylates Cys797 of EGFR, but its reactivity can cause rapid metabolic deactivation or nonspecific reactions with off-targets. We describe here a new series of irreversible inhibitors containing a 3-aminopropanamide linked in position 6 to 4-anilinoquinazoline or 4-anilinoquinoline-3- carbonitrile driving portions. Some of these compounds proved to be as efficient as their acrylamide analogues in inhibiting EGFR-TK (TK = tyrosine kinase) autophosphorylati…

Abstract LB-399: Chronic inhibition of mutant EGFR in NSCLC leads to EGFR TKI resistance by TGF-β1 mediated epithelial to mesenchymal transition

2011

Abstract In NSCLC, activating EGFR mutations underlie responsiveness of NSCLCs to reversible EGFR tyrosine kinase inhibitors (TKIs), including gefitinib and erlotinib. Despite initial responses, acquired resistance invariably develops, mediated by the emergence of the secondary T790M mutation and by focal amplification of MET, in approximately 50% and 30% of patients, respectively. The resistance mechanisms for the remaining 20% of cases remain elusive. EGFR TKI-sensitive HCC827 cells were exposed to graded concentrations of erlotinib for 6 months. Approximately 70% of the isolated clones were resistant to erlotinib and harbored MET amplification, and were sensitive to dual EGFR/MET inhibit…

β-Catenin Contributes to Lung Tumor Development Induced by EGFR Mutations

2014

Abstract The discovery of somatic mutations in EGFR and development of EGFR tyrosine kinase inhibitors (TKI) have revolutionized treatment for lung cancer. However, resistance to TKIs emerges in almost all patients and currently no effective treatment is available. Here, we show that β-catenin is essential for development of EGFR-mutated lung cancers. β-Catenin was upregulated and activated in EGFR-mutated cells. Mutant EGFR preferentially bound to and tyrosine phosphorylated β-catenin, leading to an increase in β-catenin–mediated transactivation, particularly in cells harboring the gefitinib/erlotinib-resistant gatekeeper EGFR-T790M mutation. Pharmacologic inhibition of β-catenin suppresse…

Abstract 766: Suppression of gefitinib-induced EMT in EGFR mutant NSCLC preferentially selects for acquired T790M

2015

Abstract Activating EGFR mutations in non-small lung cancer (NSCLC) confer sensitivity to reversible EGFR tyrosine kinase inhibitors (TKIs), including gefitinib and erlotinib. Despite promising initial response acquired resistance develops mediated by the emergence of the secondary T790M mutation or by focal amplification of MET. An epithelial-to-mesenchymal transition (EMT) is clinically linked to NSCLCs with acquired EGFR TKI resistance. The exact mechanisms of EGFR TKI resistance with EMT phenotype remain elusive; therefore, we attempted to develop a strategy to prevent the emergence of EGFR TKI resistance with EMT phenotype. In order to mimic the development of acquired EGFR TKI resista…

Resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer

2018

Abstract 968: β-catenin plays an important role in lung tumor development induced by EGFR mutations

2014

Abstract The discovery of somatic mutations in epidermal growth factor receptor (EGFR) and the development of EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have revolutionized treatment for non-small cell lung cancer (NSCLC). Resistance to TKIs emerges in almost all patients, but currently no effective treatment is available.Therefore, novel strategies to either prevent or overcome resistance are sorely needed. Here we show that β-catenin is essential for development of EGFR mutated lung cancers. We found that β-catenin was upregulated, translocated to the nucleus, and subsequently activated in both EGFR mutated lung cancer cell lines and EGFR mutation driven lung…