Contribution of p53 in sensitivity to EGFR tyrosine kinase inhibitors in non-small cell lung cancer.

The emergence of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) with activating EGFR mutations is a major hindrance to treatment. We investigated the effects of p53 in primary sensitivity and acquired resistance to EGFR-TKIs in NSCLC cells. Changes in sensitivity to EGFR-TKIs were determined using p53 overexpression or knockdown in cells with activating EGFR mutations.

Natural Killer Cells as a Potential Biomarker for Predicting Immunotherapy Efficacy in Patients with Non-Small Cell Lung Cancer.

Background: Immunotherapy with immune checkpoint inhibitors for non-small cell lung cancer (NSCLC) has emerged as an important treatment option. Although immunotherapy may significantly improve survival and quality of life, response rates are as low as 20% in NSCLC patients.

Objective: The identification of reliable biomarkers predicting response to immunotherapy is required urgently to determine patient selection guidelines.

Tumor-derived exosomal miR-619-5p promotes tumor angiogenesis and metastasis through the inhibition of RCAN1.4.

Tumor-derived exosomes (TEXs) contain enriched miRNAs that act as novel non-invasive biomarkers for cancer diagnosis and play a role in cancer progression. We investigated the exosomal miRNAs that affect cancer progression in non-small cell lung cancer (NSCLC) and identified the specific molecules involved. We identified that specific miRNAs in NSCLC cell-released exosomes can modulate angiogenesis, among which miR-619-5p was the most potent inducer.

Exosomal PD-L1 promotes tumor growth through immune escape in non-small cell lung cancer.

Programmed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1) pathway blockade is a promising new cancer therapy. Although PD-1/PD-L1 treatment has yielded clinical benefits in several types of cancer, further studies are required to clarify predictive biomarkers for drug efficacy and to understand the fundamental mechanism of PD-1/PD-L1 interaction between host and tumor cells. Here, we show that exosomes derived from lung cancer cells express PD-L1 and play a role in immune escape by reducing T-cell activity and promoting tumor growth.

Enhanced Glycolysis Supports Cell Survival in EGFR-Mutant Lung Adenocarcinoma by Inhibiting Autophagy-Mediated EGFR Degradation.

Oncogenic EGFR is essential for the development and growth of non-small cell lung cancer (NSCLC), but the precise roles of EGFR in lung cancer metabolism remain unclear. Here, we show that EGFR mutation-mediated enhancement of glycolysis is critical for EGFR stability. EGFR knockdown significantly decreased levels of glycolytic pathway intermediates via transcriptional regulation of glycolytic genes.

Discovery of a Potent and Mutant-Selective EGFR Inhibitor that Overcomes T790M-Mediated Resistance in Lung Cancer.

Background: Despite remarkable activity in epidermal growth factor receptor (EGFR)-mutant lung cancer patients, the clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) is limited by the emergence of acquired resistance, which is mostly caused by a secondary T790M mutation. Fortunately, newly developed, mutant-selective EGFR-TKIs against T790M have been proven as an effective therapeutic approach although only osimertinib has received the FDA approval until now.

Objective: To determine the in vitro and in vivo efficacy of a new EGFR TKI, OBX1-012 in cells with mutant EGFR.

Multiple receptor tyrosine kinase activation related to ALK inhibitor resistance in lung cancer cells with ALK rearrangement.

The activation of alternative receptor tyrosine kinases (RTKs) is known to mediate resistance to ALK inhibitors. However, the role of multiple RTK activation in resistance has yet to be determined. Two crizotinib-resistant (H3122/CR-1 and H3122/CR-2) and one TAE684-resistant (H2228/TR) cell lines were established.

Activation of the IGF1R pathway potentially mediates acquired resistance to mutant-selective 3rd-generation EGF receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer.

Mutant-selective, 3rd-generation EGFR-TKIs were recently developed to control lung cancer cells harboring T790M-mediated resistance. However, the development of resistance to these novel drugs seems inevitable. Thus, we investigated the mechanism of acquired resistance to the mutant-selective EGFR-TKI WZ4002.

AUY922 effectively overcomes MET- and AXL-mediated resistance to EGFR-TKI in lung cancer cells.

The activation of bypass signals, such as MET and AXL, has been identified as a possible mechanism of EGFR-TKI resistance. Because various oncoproteins depend on HSP90 for maturation and stability, we investigated the effects of AUY922, a newly developed non-geldanamycin class HSP90 inhibitor, in lung cancer cells with MET- and AXL-mediated resistance. We established resistant cell lines with HCC827 cells harboring an exon 19-deletion mutation in of the EGFR gene via long-term exposure to increasing concentrations of gefitinib and erlotinib (HCC827/GR and HCC827/ER, respectively).

AKT/mTOR down-regulation by CX-4945, a CK2 inhibitor, promotes apoptosis in chemorefractory non-small cell lung cancer cells.

Aim: The response to chemotherapeutic drugs in non-small cell lung cancer (NSCLC) is unsatisfactory, leading to poor outcomes. This study the aimed to investigates anticancer effects of CX-4945, a potent casein kinase II (CK2) inhibitor, in chemorefractory NSCLC cells.

Materials And Methods: Cell proliferation and apoptosis assay were carried-out by annexin V-FITC and FACScan after drug treatment with paclitaxel, cisplatin and CX-4945.

MET and AXL inhibitor NPS-1034 exerts efficacy against lung cancer cells resistant to EGFR kinase inhibitors because of MET or AXL activation.

In non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations, acquired resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKI) can occur through a generation of bypass signals such as MET or AXL activation. In this study, we investigated the antitumor activity of NPS-1034, a newly developed drug that targets both MET and AXL, in NSCLC cells with acquired resistance to gefitinib or erlotinib (HCC827/GR and HCC827/ER, respectively). Characterization of H820 cells and evaluation of NPS-1034 efficacy in these cells were also performed.

Neuroendocrine differentiation in acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor.

Background: Small cell lung cancer (SCLC) transformation during epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment in lung cancer has been suggested as one of possible resistance mechanisms.

Methods: We evaluated whether SCLC transformation or neuroendocrine (NE) differentiation can be found in the cell line model. In addition, we also investigated its effect on responses to conventional chemotherapeutic drugs of the SCLC treatment.

Ethyl pyruvate stabilizes hypoxia-inducible factor 1 alpha via stimulation of the TCA cycle.

Ethyl pyruvate is a simple derivative of the endogenous metabolite pyruvate. Pyruvate is the starting substrate for the tricarboxylic acid (TCA) cycle and plays a central role in intermediary metabolism. The present study was to determine whether ethyl pyruvate affects the expression of hypoxia-inducible factor 1 alpha (HIF-1alpha) and to explore the mechanism of HIF-1alpha regulation.

Okadaic acid promotes angiogenesis via activation of hypoxia-inducible factor-1.

Okadaic acid, a potent tumor promoter and an inhibitor of protein phosphatase 1 and 2A, has also been characterized as an angiogenic inducer in the chorioallantoic membrane of the chick embryo. To elucidate the roles of okadaic acid on angiogenic processes, we conducted in vitro angiogenesis assays. In this study, we report that okadaic acid potently stimulated tube formation, migration, and invasion of human umbilical vein endothelial cells.

Okadaic acid protects human neuroblastoma SH-SY5Y cells from 1-methyl-4-phenylpyridinium ion-induced apoptosis.

1-methyl-4-phenylpyridinium ion (MPP(+)) has been shown to selectively inhibit mitochondrial function and induce a parkinsonism-like syndrome. MPP(+) stimulates the production of reactive oxygen species (ROS) and induces cell death in vitro. In this study, we investigated the protective effects of okadaic acid on MPP(+)-induced cell death in SH-SY5Y neuroblastoma cells.