Dual inhibition of MEK and p38 impairs tumor growth in KRAS‑mutated non‑small cell lung cancer

Sunaga,Noriaki; Miura,Yosuke; Tsukagoshi,Yusuke; Kasahara,Norimitsu; Masuda,Tomomi; Sakurai,Reiko; Kaira,Kyoichi; Hisada,Takeshi

doi:10.3892/ol.2019.10009

Dual inhibition of MEK and p38 impairs tumor growth in KRAS‑mutated non‑small cell lung cancer

Authors:
- Noriaki Sunaga
- Yosuke Miura
- Yusuke Tsukagoshi
- Norimitsu Kasahara
- Tomomi Masuda
- Reiko Sakurai
- Kyoichi Kaira
- Takeshi Hisada
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Affiliations: Department of Respiratory Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma 371‑8511, Japan, Innovative Medical Research Center, Gunma University Hospital, Maebashi, Gunma 371‑8511, Japan, Oncology Center, Gunma University Hospital, Maebashi, Gunma 371‑8511, Japan, Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama Medical University, Hidaka, Saitama 350‑1298, Japan
Published online on: February 4, 2019 https://doi.org/10.3892/ol.2019.10009
Pages: 3569-3575

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Abstract

Despite the high frequency of KRAS mutations in non‑small cell lung cancer (NSCLC), therapeutic modalities targeting KRAS‑mutated NSCLC have not been established. Based on our previous findings that mutant KRAS knockdown sensitized NSCLC cells to a p38 inhibitor, the growth‑inhibitory effect of dual MEK and p38 inhibition on tumor growth in NSCLC cells harboring KRAS mutations was investigated. In KRAS‑mutated NSCLC cells, the MEK inhibitor, selumetinib, inhibited cell growth in a dose‑dependent manner, and its growth‑inhibitory effect was enhanced by combined treatment with the p38 inhibitor LY2228820. Similarly, another pair of MEK and p38 inhibitors also exhibited antitumor activity. Small interfering RNAs (siRNAs) against MAPK14, which encodes p38α MAPK, enhanced the growth‑inhibitory effect of the MEK inhibitors in NSCLC cells with KRAS mutations. Notably, MEK inhibitors reduced p38 expression levels but increased p38 phosphorylation levels, resulting in sensitization to p38 inhibitors in KRAS‑mutated NSCLC cells. These results provide evidence that dual MEK and p38 inhibition could be a potent therapeutic strategy against oncogenic KRAS‑driven NSCLC.

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