MEK Inhibition Modulates Cytokine Response to Mediate Therapeutic Efficacy in Lung Cancer.

ABSTRACT: Activating mutations in BRAF, a key mediator of RAS signaling, are present in approximately 50% of melanoma patients. Pharmacologic inhibition of BRAF or the downstream MAP kinase MEK is 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-?B activity. MEKi potentiated the response to TNF?, a potent activator of NF-?B. In both melanoma and lung cancer cells, MEKi increased cell-surface expression of TNF? receptor 1 (TNFR1), which enhanced NF-?B activation and augmented expression of genes regulated by TNF? and IFN?. Screening of 289 targeted agents for the ability to increase TNF? and IFN? 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 TNF? and IFN?-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 antitumor efficacy of MEKi, whereas the administration of TNF? and IFN? in MEKi-treated mice enhanced the antitumor 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 that can be therapeutically exploited. SIGNIFICANCE: Lung cancer cells are rendered sensitive to MEK inhibitors by TNF? and IFN?, providing a strong mechanistic rationale for combining immunotherapeutics, such as checkpoint blockers, with MEK inhibitor therapy for lung cancer.See related commentary by Havel, p. 5699.

SUBMITTER: Xie M 

PROVIDER: S-EPMC6881545 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature