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Article

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
  • View Affiliations / Copyright

    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
  • Pages: 3569-3575
    |
    Published online on: February 4, 2019
       https://doi.org/10.3892/ol.2019.10009
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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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1 

Siegel RL, Miller KD and Jemal A: Cancer statistics, 2018. CA Cancer J Clin. 68:7–30. 2018. View Article : Google Scholar : PubMed/NCBI

2 

Houston KA, Henley SJ, Li J, White MC and Richards TB: Patterns in lung cancer incidence rates and trends by histologic type in the United States, 2004–2009. Lung Cancer. 86:22–28. 2014. View Article : Google Scholar : PubMed/NCBI

3 

Herbst RS, Morgensztern D and Boshoff C: The biology and management of non-small cell lung cancer. Nature. 553:446–454. 2018.PubMed/NCBI

4 

Saito M, Shiraishi K, Kunitoh H, Takenoshita S, Yokota J and Kohno T: Gene aberrations for precision medicine against lung adenocarcinoma. Cancer Sci. 107:713–720. 2016. View Article : Google Scholar : PubMed/NCBI

5 

Kris MG, Johnson BE, Berry LD, Kwiatkowski DJ, Iafrate AJ, Wistuba II, Varella-Garcia M, Franklin WA, Aronson SL, Su PF, et al: Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 311:1998–2006. 2014. View Article : Google Scholar : PubMed/NCBI

6 

Pylayeva-Gupta Y, Grabocka E and Bar-Sagi D: RAS oncogenes: Weaving a tumorigenic web. Nat Rev Cancer. 11:761–774. 2011. View Article : Google Scholar : PubMed/NCBI

7 

Meng D, Yuan M, Li X, Chen L, Yang J, Zhao X, Ma W and Xin J: Prognostic value of K-RAS mutations in patients with non-small cell lung cancer: A systematic review with meta-analysis. Lung Cancer. 81:1–10. 2013. View Article : Google Scholar : PubMed/NCBI

8 

Ying M, Zhu XX, Zhao Y, Li DH and Chen LH: KRAS mutation as a biomarker for survival in patients with non-small cell lung cancer, a meta-analysis of 12 randomized trials. Asian Pac J Cancer Prev. 16:4439–4445. 2015. View Article : Google Scholar : PubMed/NCBI

9 

Matikas A, Mistriotis D, Georgoulias V and Kotsakis A: Targeting KRAS mutated non-small cell lung cancer: A history of failures and a future of hope for a diverse entity. Crit Rev Oncol Hematol. 110:1–12. 2017. View Article : Google Scholar : PubMed/NCBI

10 

Blumenschein GR Jr, Smit EF, Planchard D, Kim DW, Cadranel J, De Pas T, Dunphy F, Udud K, Ahn MJ, Hanna NH, et al: A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)†. Ann Oncol. 26:894–901. 2015. View Article : Google Scholar : PubMed/NCBI

11 

Jänne PA, van den Heuvel MM, Barlesi F, Cobo M, Mazieres J, Crinò L, Orlov S, Blackhall F, Wolf J, Garrido P, et al: Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer: The SELECT-1 randomized clinical trial. JAMA. 317:1844–1853. 2017. View Article : Google Scholar : PubMed/NCBI

12 

Sunaga N, Shames DS, Girard L, Peyton M, Larsen JE, Imai H, Soh J, Sato M, Yanagitani N, Kaira K, et al: Knockdown of oncogenic KRAS in non-small cell lung cancers suppresses tumor growth and sensitizes tumor cells to targeted therapy. Mol Cancer Ther. 10:336–346. 2011. View Article : Google Scholar : PubMed/NCBI

13 

Sunaga N, Kaira K, Imai H, Shimizu K, Nakano T, Shames DS, Girard L, Soh J, Sato M, Iwasaki Y, et al: Oncogenic KRAS-induced epiregulin overexpression contributes to aggressive phenotype and is a promising therapeutic target in non-small-cell lung cancer. Oncogene. 32:4034–4042. 2013. View Article : Google Scholar : PubMed/NCBI

14 

Sunaga N, Imai H, Shimizu K, Shames DS, Kakegawa S, Girard L, Sato M, Kaira K, Ishizuka T, Gazdar AF, et al: Oncogenic KRAS-induced interleukin-8 overexpression promotes cell growth and migration and contributes to aggressive phenotypes of non-small cell lung cancer. Int J Cancer. 130:1733–1744. 2012. View Article : Google Scholar : PubMed/NCBI

15 

Zhang W and Liu HT: MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 12:9–18. 2002. View Article : Google Scholar : PubMed/NCBI

16 

Heigener DF, Gandara DR and Reck M: Targeting of MEK in lung cancer therapeutics. Lancet Respir Med. 3:319–327. 2015. View Article : Google Scholar : PubMed/NCBI

17 

Cuadrado A and Nebreda AR: Mechanisms and functions of p38 MAPK signalling. Biochem J. 429:403–417. 2010. View Article : Google Scholar : PubMed/NCBI

18 

Loesch M and Chen G: The p38 MAPK stress pathway as a tumor suppressor or more? Front Biosci. 13:3581–3593. 2008. View Article : Google Scholar : PubMed/NCBI

19 

Sui X, Kong N, Ye L, Han W, Zhou J, Zhang Q, He C and Pan H: p38 and JNK MAPK pathways control the balance of apoptosis and autophagy in response to chemotherapeutic agents. Cancer Lett. 344:174–179. 2014. View Article : Google Scholar : PubMed/NCBI

20 

Chiacchiera F, Grossi V, Cappellari M, Peserico A, Simonatto M, Germani A, Russo S, Moyer MP, Resta N, Murzilli S and Simone C: Blocking p38/ERK crosstalk affects colorectal cancer growth by inducing apoptosis in vitro and in preclinical mouse models. Cancer Lett. 324:98–108. 2012. View Article : Google Scholar : PubMed/NCBI

21 

van Houdt WJ, de Bruijn MT, Emmink BL, Raats D, Hoogwater FJ, Borel Rinkes IH and Kranenburg O: Oncogenic K-ras activates p38 to maintain colorectal cancer cell proliferation during MEK inhibition. Cell Oncol. 32:245–257. 2010.PubMed/NCBI

22 

Wright LN, Ryscavage A, Merlino G and Yuspa SH: Modeling the transcriptional consequences of epidermal growth factor receptor ablation in Ras-initiated squamous cancer. Clin Cancer Res. 18:170–183. 2012. View Article : Google Scholar : PubMed/NCBI

23 

Miura Y and Sunaga N: Role of immunotherapy for oncogene-driven non-small cell lung cancer. Cancers (Basel). 10(pii): E2452018. View Article : Google Scholar : PubMed/NCBI

24 

Tolcher AW, Khan K, Ong M, Banerji U, Papadimitrakopoulou V, Gandara DR, Patnaik A, Baird RD, Olmos D, Garrett CR, et al: Antitumor activity in RAS-driven tumors by blocking AKT and MEK. Clin Cancer Res. 21:739–748. 2015. View Article : Google Scholar : PubMed/NCBI

25 

Tao Z, Le Blanc JM, Wang C, Zhan T, Zhuang H, Wang P, Yuan Z and Lu B: Coadministration of trametinib and palbociclib radiosensitizes KRAS-mutant non-small cell lung cancers in vitro and in vivo. Clin Cancer Res. 22:122–133. 2016. View Article : Google Scholar : PubMed/NCBI

26 

Park KS, Oh B, Lee MH, Nam KY, Jin HR, Yang H, Choi J, Kim SW and Lee DH: The HSP90 inhibitor, NVP-AUY922, sensitizes KRAS-mutant non-small cell lung cancer with intrinsic resistance to MEK inhibitor, trametinib. Cancer Lett. 372:75–81. 2016. View Article : Google Scholar : PubMed/NCBI

27 

Manchado E, Weissmueller S, Morris JP IV, Chen CC, Wullenkord R, Lujambio A, de Stanchina E, Poirier JT, Gainor JF, Corcoran RB, et al: A combinatorial strategy for treating KRAS-mutant lung cancer. Nature. 534:647–651. 2016. View Article : Google Scholar : PubMed/NCBI

28 

Kitai H, Ebi H, Tomida S, Floros KV, Kotani H, Adachi Y, Oizumi S, Nishimura M, Faber AC and Yano S: Epithelial-to-mesenchymal transition defines feedback activation of receptor tyrosine kinase signaling induced by MEK inhibition in KRAS-mutant lung cancer. Cancer Discov. 6:754–769. 2016. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Sunaga N, Miura Y, Tsukagoshi Y, Kasahara N, Masuda T, Sakurai R, Kaira K and Hisada T: Dual inhibition of MEK and p38 impairs tumor growth in KRAS‑mutated non‑small cell lung cancer. Oncol Lett 17: 3569-3575, 2019.
APA
Sunaga, N., Miura, Y., Tsukagoshi, Y., Kasahara, N., Masuda, T., Sakurai, R. ... Hisada, T. (2019). Dual inhibition of MEK and p38 impairs tumor growth in KRAS‑mutated non‑small cell lung cancer. Oncology Letters, 17, 3569-3575. https://doi.org/10.3892/ol.2019.10009
MLA
Sunaga, N., Miura, Y., Tsukagoshi, Y., Kasahara, N., Masuda, T., Sakurai, R., Kaira, K., Hisada, T."Dual inhibition of MEK and p38 impairs tumor growth in KRAS‑mutated non‑small cell lung cancer". Oncology Letters 17.3 (2019): 3569-3575.
Chicago
Sunaga, N., Miura, Y., Tsukagoshi, Y., Kasahara, N., Masuda, T., Sakurai, R., Kaira, K., Hisada, T."Dual inhibition of MEK and p38 impairs tumor growth in KRAS‑mutated non‑small cell lung cancer". Oncology Letters 17, no. 3 (2019): 3569-3575. https://doi.org/10.3892/ol.2019.10009
Copy and paste a formatted citation
x
Spandidos Publications style
Sunaga N, Miura Y, Tsukagoshi Y, Kasahara N, Masuda T, Sakurai R, Kaira K and Hisada T: Dual inhibition of MEK and p38 impairs tumor growth in KRAS‑mutated non‑small cell lung cancer. Oncol Lett 17: 3569-3575, 2019.
APA
Sunaga, N., Miura, Y., Tsukagoshi, Y., Kasahara, N., Masuda, T., Sakurai, R. ... Hisada, T. (2019). Dual inhibition of MEK and p38 impairs tumor growth in KRAS‑mutated non‑small cell lung cancer. Oncology Letters, 17, 3569-3575. https://doi.org/10.3892/ol.2019.10009
MLA
Sunaga, N., Miura, Y., Tsukagoshi, Y., Kasahara, N., Masuda, T., Sakurai, R., Kaira, K., Hisada, T."Dual inhibition of MEK and p38 impairs tumor growth in KRAS‑mutated non‑small cell lung cancer". Oncology Letters 17.3 (2019): 3569-3575.
Chicago
Sunaga, N., Miura, Y., Tsukagoshi, Y., Kasahara, N., Masuda, T., Sakurai, R., Kaira, K., Hisada, T."Dual inhibition of MEK and p38 impairs tumor growth in KRAS‑mutated non‑small cell lung cancer". Oncology Letters 17, no. 3 (2019): 3569-3575. https://doi.org/10.3892/ol.2019.10009
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