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Cancer Res. 2019 Jul 30. pii: canres.0698.2019. doi: 10.1158/0008-5472.CAN-19-0698. [Epub ahead of print]

MEK inhibition modulates cytokine response to mediate therapeutic efficacy in lung cancer.

Author information

1
Immunology, Moffitt Cancer Center.
2
Molecular Oncology Department, Moffitt Cancer Center and Research Institute.
3
Emory Vaccine Center, Emory University.
4
Molecular Oncology Program, H. Lee Moffitt Cancer Center & Research Institute.
5
Department of Biostatistics and Bioinformatics, Moffitt Cancer Center.
6
Drug Discovery, Moffitt Cancer Center.
7
NIAID, National Institutes of Health.
8
Tumor Biology, Moffitt Cancer Center.
9
Department of Thoracic Oncology, Moffitt Cancer Center.
10
Immunology, H. Lee Moffitt Cancer Center & Research Institute Amer.Beg@moffitt.org.

Abstract

Activating mutations in BRAF, a key mediator of RAS signaling, are present in ~50% of melanoma patients. Pharmacological inhibition of BRAF or the downstream MAP kinase MEK are highly effective in treating BRAF-mutant melanoma. In contrast, RAS pathway inhibitors have been less effective in treating epithelial malignancies, such as lung cancer. Here, we show that treatment of melanoma patients with BRAF and MEK inhibitors (MEKi) activated tumor NF-kB activity. MEKi potentiated the response to TNFa, a potent activator of NF-kB. In both melanoma and lung cancer cells, MEKi increased cell surface expression of TNFα receptor 1 (TNFR1), which enhanced NF-kB activation and augmented expression of genes regulated by TNFa and IFNg. Screening of 289 targeted agents for the ability to increase TNFa and IFNg target gene expression demonstrated that this was a general activity of inhibitors of MEK and ERK kinases. Treatment with MEKi led to acquisition of a novel vulnerability to TNFa and IFNg-induced apoptosis in lung cancer cells that were refractory to MEKi killing and augmented cell cycle arrest. Abolishing the expression of TNFR1 on lung cancer cells impaired the anti-tumor efficacy of MEKi while the administration of TNFa and IFNg in MEKi-treated mice enhanced the anti-tumor response. Furthermore, immunotherapeutics known to induce expression of these cytokines synergized with MEKi in eradicating tumors. These findings define a novel cytokine response modulatory function of MEKi which can be therapeutically exploited.

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