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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Inhibition of Mitogen-Activated Protein Kinase Kinase Alone and in Combination with Anaplastic Lymphoma Kinase (ALK) Inhibition Suppresses Tumor Growth in a Mouse Model of ALK-Positive Lung Cancer

N. Shrestha, A.R. Bland, R.L. Bower, R.J. Rosengren and J.C. Ashton
Journal of Pharmacology and Experimental Therapeutics July 2020, 374 (1) 134-140; DOI: https://doi.org/10.1124/jpet.120.266049
N. Shrestha
Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
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A.R. Bland
Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
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R.L. Bower
Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
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R.J. Rosengren
Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
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J.C. Ashton
Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
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Abstract

Anaplastic lymphoma kinase (ALK)-positive non–small-cell lung cancer most commonly arises through EML4 (Echinoderm Microtuble Like 4)-ALK chromosomal fusion. We have previously demonstrated that combination of the ALK inhibitor crizotinib with the MEK inhibitor selumetinib was highly effective at reducing cell viability of ALK-positive non–small-cell lung cancer (H3122) cells. In this study, we further investigated the efficacy of crizotinib and selumetinib combination therapy in an in vivo xenograft model of ALK-positive lung cancer. Crizotinib decreased tumor volume by 52% compared with control, and the drug combination reduced tumor growth compared with crizotinib. In addition, MEK inhibition alone reduced tumor growth by 59% compared with control. Crizotinib and selumetinib alone and in combination were nontoxic at the dose of 25 mg/kg, with values for ALT (<80 U/l) and creatinine (<2 mg/dl) within the normal range. Our results support the combined use of crizotinib with selumetinib in ALK-positive lung cancer but raise the possibility that a sufficient dose of an MEK inhibitor alone may be as effective as adding an MEK inhibitor to an ALK inhibitor.

SIGNIFICANCE STATEMENT This study contains in vivo evidence supporting the use of combination MEK inhibitors in ALK+ lung cancer research, both singularly and in combination with ALK inhibitors. Contrary to previously published reports, our results suggest that it is possible to gain much of the benefit from combination treatment with an MEK inhibitor alone, at a tolerable dose.

Footnotes

    • Received March 1, 2020.
    • Accepted April 8, 2020.
  • This work was supported by a University of Otago Research Grant (Grant 0119-0520).

  • https://doi.org/10.1124/jpet.120.266049.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 374 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 374, Issue 1
1 Jul 2020
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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

MEK for ALK-Positive Lung Cancer

N. Shrestha, A.R. Bland, R.L. Bower, R.J. Rosengren and J.C. Ashton
Journal of Pharmacology and Experimental Therapeutics July 1, 2020, 374 (1) 134-140; DOI: https://doi.org/10.1124/jpet.120.266049

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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

MEK for ALK-Positive Lung Cancer

N. Shrestha, A.R. Bland, R.L. Bower, R.J. Rosengren and J.C. Ashton
Journal of Pharmacology and Experimental Therapeutics July 1, 2020, 374 (1) 134-140; DOI: https://doi.org/10.1124/jpet.120.266049
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