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Targeting of both PI3K/Akt/mTOR pathway and mutant EGFR to overcome resistance to tyrosine kinase inhibitors in mutant EGFR-mediated lung cancer

Xiaoling Song


Lung cancer is a leading cause of cancer-related death worldwide and in the United States. Targeted therapy of treating mutant Epidermal Growth Factor Receptor (EGFR) mediated lung cancer with tyrosine kinase inhibitors (TKI) has greatly improved clinical response. However, these lung tumors inevitably develop resistance to these TKI drugs within a year, which restricts the improvement in treatment outcome. Identified resistant mechanisms include acquiring a secondary T790M resistant mutation on EGFR, PI3KCA mutation, amplification of MET tyrosine receptor or overexpression of MET ligand HGF. Almost all of these resistant mechanisms relate to a sustained activation of phosphatidylinositol 3-kinase (PI3K)/ Akt pathway in tumors cells in the presence of EGFR TKIs. Studies showed that inhibitors of PI3K/mTOR pathway regulated the growth of EGFR TKI-sensitive mutant lung cancer cell lines and potentiate or enhance the effect of irreversible EGFR TKIs on growth inhibition in resistant EGFR mutant lung cancer cell lines and in xenograft model. Data reviewed in this literature suggested the combined treatment of PI3K/mTOR inhibitor with EGFR TKI provides a promising way to overcome of EGFR TKI resistant and improve therapeutic outcome.


EGFR mutant lung cancer, TKI resistance, PI3K/AKT pathway, mTOR inhibitor, tumor regression

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