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

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 BRAFmutant 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-kappa B activity. MEKi potentiated the response to TNF alpha, a potent activator of NF-kappa B. In both melanoma and lung cancer cells, MEKi increased cellsurface expression of TNF alpha receptor 1 (TNFR1), which enhanced NF-kappa B activation and augmented expression of genes regulated by TNF alpha and IFN gamma. Screening of 289 targeted agents for the ability to increase TNF alpha and IFN gamma 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 alpha and IFN gamma-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 alpha and IFN gamma 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 toMEK inhibitors by TNF alpha and IFN gamma, providing a strong mechanistic rationale for combining immunotherapeutics, such as checkpoint blockers, with MEK inhibitor therapy for lung cancer.