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-κB activity. MEKi potentiated the response to TNFα, a potent activator of NF-κB. In both melanoma and lung cancer cells, MEKi increased cell-surface expression of TNFα receptor 1 (TNFR1), which enhanced NF-κB activation and augmented expression of genes regulated by TNFα and IFNγ. Screening of 289 targeted agents for the ability to increase TNFα and IFNγ 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 TNFα and IFNγ-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 TNFα and IFNγ 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 15, 2019
- Source ID
- 10.1158/0008-5472.can-19-0698
Entities
People
- Amer A. Beg
- Eric B. Haura
- Fumi Kinose
- Hong Zheng
- Keiran S.m. Smalley
- Mengyu Xie
- Nicholas T. Gimbrone
- Ranjna Madan-lala
- Sarah A. Blackstone
- Uwe Rix
- W. Douglas Cress
- Wenjie Dai
- Zhihua Chen
Organizations
- H. Lee Moffitt Cancer Center & Research Institute
- National Institutes of Health
- University of South Florida