Open AccessCombined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR‐TKIs in non‐small cell lung cancer
Author(s) -
Sato Hiroki,
Yamamoto Hiromasa,
Sakaguchi Masakiyo,
Shien Kazuhiko,
Tomida Shuta,
Shien Tadahiko,
Ikeda Hirokuni,
Hatono Minami,
Torigoe Hidejiro,
Namba Kei,
Yoshioka Takahiro,
Kurihara Eisuke,
Ogoshi Yusuke,
Takahashi Yuta,
Soh Junichi,
Toyooka Shinichi
Publication year - 2018
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13763
Subject(s) - cancer research , pi3k/akt/mtor pathway , mapk/erk pathway , t790m , epithelial–mesenchymal transition , trametinib , protein kinase b , egfr inhibitors , mek inhibitor , targeted therapy , epidermal growth factor receptor , medicine , combination therapy , signal transduction , biology , cancer , gefitinib , microbiology and biotechnology , metastasis
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.