Cancer science, 2018-10, Vol.109 (10), p.3183-3196
2018
Details
- Autor(en) / Beteiligte
- Titel
- Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR‐TKIs in non‐small cell lung cancer
- Ist Teil von
- Cancer science, 2018-10, Vol.109 (10), p.3183-3196
- Ort / Verlag
- England: John Wiley & Sons, Inc
- Erscheinungsjahr
- 2018
- Link zum Volltext
- Quelle
- Wiley Online Library Journals Frontfile Complete
- Beschreibungen/Notizen
- Compensatory activation of the signal transduction pathways is one of the major obstacles for the targeted therapy of non‐small cell lung cancer (NSCLC). Herein, we present the therapeutic strategy of combined targeted therapy against the MEK and phosphoinositide‐3 kinase (PI3K) pathways for acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC. We investigated the efficacy of combined trametinib plus taselisib therapy using experimentally established EGFR‐TKI‐resistant NSCLC cell lines. The results showed that the feedback loop between MEK/ERK and PI3K/AKT pathways had developed in several resistant cell lines, which caused the resistance to single‐agent treatment with either inhibitor alone. Meanwhile, the combined therapy successfully regulated the compensatory activation of the key intracellular signals and synergistically inhibited the cell growth of those cells in vitro and in vivo. The resistance mechanisms for which the dual kinase inhibitor therapy proved effective included (MET) mesenchymal‐epithelial transition factor amplification, induction of epithelial‐to‐mesenchymal transition (EMT) and EGFR T790M mutation. In further analysis, the combination therapy induced the phosphorylation of p38 MAPK signaling, leading to the activation of apoptosis cascade. Additionally, long‐term treatment with the combination therapy induced the conversion from EMT to mesenchymal‐to‐epithelial transition in the resistant cell line harboring EMT features, restoring the sensitivity to EGFR‐TKI. In conclusion, our results indicate that the combined therapy using MEK and PI3K inhibitors is a potent therapeutic strategy for NSCLC with the acquired resistance to EGFR‐TKIs. Effect of MEK/PI3K dual blockade was examined using EGFR‐TKI‐resistant NSCLC cells. Single‐agent therapies led to the compensatory activation of other pathways. Combination therapy inhibited the growth of resistant cells in vitro and in vivo
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1347-9032eISSN: 1349-7006DOI: 10.1111/cas.13763Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6172047
- Format
- –
- Schlagworte
- 1-Phosphatidylinositol 3-kinase, acquired resistance, AKT protein, Animals, Antineoplastic Combined Chemotherapy Protocols - pharmacology, Antineoplastic Combined Chemotherapy Protocols - therapeutic use, Apoptosis, c-Met protein, Carcinoma, Non-Small-Cell Lung - drug therapy, Carcinoma, Non-Small-Cell Lung - pathology, Cell activation, Cell growth, Cell Line, Tumor, Cell Proliferation - drug effects, Clinical trials, compensatory activation, Drug resistance, Drug Resistance, Neoplasm - drug effects, Drug Resistance, Neoplasm - genetics, Drug Synergism, Enzyme inhibitors, Epidermal growth factor, Epidermal growth factor receptors, Epithelial-Mesenchymal Transition - drug effects, ErbB Receptors - antagonists & inhibitors, ErbB Receptors - genetics, Extracellular signal-regulated kinase, Feedback, Female, Humans, Imidazoles - pharmacology, Imidazoles - therapeutic use, Lung cancer, Lung Neoplasms - drug therapy, Lung Neoplasms - pathology, MAP kinase, MEK inhibitor, Mesenchyme, Mice, Inbred BALB C, Mice, Nude, Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors, Mitogen-Activated Protein Kinase Kinases - metabolism, Mutation, Non-small cell lung carcinoma, non‐small cell lung cancer, Original, Oxazepines - pharmacology, Oxazepines - therapeutic use, Phosphatidylinositol 3-Kinases - metabolism, Phosphoinositide-3 Kinase Inhibitors, Phosphorylation, PI3K inhibitor, Protein Kinase Inhibitors - pharmacology, Protein Kinase Inhibitors - therapeutic use, Protein-tyrosine kinase, Pyridones - pharmacology, Pyridones - therapeutic use, Pyrimidinones - pharmacology, Pyrimidinones - therapeutic use, Signal transduction, Signal Transduction - drug effects, Stem cells, Tumors, Xenograft Model Antitumor Assays