Authors: Mengyu Xie, Hong Zheng, Ranjna Madan-Lala, Wenjie Dai, Nicholas T Gimbrone, Zhihua Chen, Fumi Kinose, Sarah A Blackstone, Keiran S.M. Smalley, W. Douglas Cress, Eric B Haura, Uwe Rix, Amer A Beg
Summary: 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.
Source: Cancer Research, 2019; canres.0698.2019