ArticleCancer science2018
Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer.
Article in Cancer science, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 65 citations in OpenAlex.
- Anoikis in cancer: molecular mechanisms, resistance, and therapeutic strategies.Apoptosis : an international journal on programmed cell death · 2026Review
- The mechanistic role of the thromboxane A2 receptor (TBXA2R) in non-small cell lung cancer (NSCLC).Cancer cell international · 2026Article
- Article
- Combined treatment of TKIs with Cilengitide overcomes afatinib-resistance in EGFR-mutated NSCLC cells.Molecular biology reports · 2025Article
- Endoplasmic reticulum stress-related genes play a role in the prognosis of lung adenocarcinoma.Discover oncology · 2025Article
- Matrix metalloproteinase-driven epithelial-mesenchymal transition: implications in health and disease.Journal of translational medicine · 2025Review
- Synthetic Lethality of SHP2 and XIAP Suppresses Proliferation and Metastasis in KRAS-mutant Nonsmall Cell Lung Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Integrative transcriptomic analysis identifies emetine as a promising candidate for overcoming acquired resistance to ALK inhibitors in lung cancer.Molecular oncology · 2025Article
- Targeting PI3K signaling in Lung Cancer: advances, challenges and therapeutic opportunities.Journal of translational medicine · 2025Review
- tRF3a-MetCAT Promotes EGFR-Targeted Therapeutic Resistance through the TRIM21-STAT1-C5a Axis in Lung Adenocarcinoma.Research (Washington, D.C.) · 2025Article
- Differential Responses to Targeted Therapies in Non-Small Cell Lung Cancer: A Comparative Analysis of Outcomes in Patients with Single EGFR Mutation and Concurrent Gene Alterations.The application of clinical genetics · 2025Article
- Predicting treatment outcome using kinome activity profiling in HER2+ breast cancer biopsies.iScience · 2024Article
- Mechanisms of resistance to targeted therapy and immunotherapy in non-small cell lung cancer: promising strategies to overcoming challenges.Frontiers in immunology · 2024Review
- Review
- Treatment of advanced non-small cell lung cancer with driver mutations: current applications and future directions.Frontiers of medicine · 2023Review
- CBX5 loss drives EGFR inhibitor resistance and results in therapeutically actionable vulnerabilities in lung cancer.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- To explore the effect of kaempferol on non-small cell lung cancer based on network pharmacology and molecular docking.Frontiers in pharmacology · 2023Article
- The Biology and Therapeutic Potential of the Src-YAP Axis in Non-Small Cell Lung Cancer (NSCLC).Cancers · 2022Article
- Multiple primary lung cancer tumors with diversified genetic mutations-complications in choosing therapeutic options.Clinical and translational discovery · 2022Article
- Crosstalk between protein kinases AKT and ERK1/2 in human lung tumor-derived cell models.Frontiers in oncology · 2022Article
Corrections and comments
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Authors and funding
16 authors at 1 institution in 1 country.
Funding
Abstract
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.
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