Cell-Selective Inhibition of NF-κB Signaling Improves Therapeutic Index in a Melanoma Chemotherapy Model

The transcription factor NF-kappa B promotes the survival of cancer cells exposed to doxorubicin and other chemotherapeutic agents. I kappa B kinase is essential for chemotherapy-induced NF-kappa B activation and considered a prime target for anticancer treatment. An I kappa B kinase inhibitor sensitized human melanoma xenografts in mice to killing by doxorubicin yet also exacerbated treatment toxicity in the host animals. By using mouse models that simulate cell-selective targeting, we found that impaired NF-kappa B activation in melanoma and host myeloid cells accounts for therapeutic and adverse effects, respectively. Ablation of tumor-intrinsic NF-kappa B activity resulted in apoptosis-driven tumor regression after treatment with doxorubicin. By contrast, chemotherapy in mice with myeloid-specific loss of NF-kappa B activation led to a massive intratumoral recruitment of interleukin-1 beta-producing neutrophils and necrotic tumor lesions, a condition associated with increased host mortality but not accompanied by tumor regression. Therefore, a molecular target-based therapy may be steered toward different clinical outcomes depending on the drug's cell-specific effects. SIGNIFICANCE: Our findings show that the I kappa B kinase-NF-kappa B signaling pathway is important for both promoting treatment resistance and preventing host toxicity in cancer chemotherapy; however, the two functions are exerted by distinct cell type-specific mechanisms and can therefore be selectively targeted to achieve an improved therapeutic outcome. Cancer Discovery; 1(6); 496-507. (C) 2011 AACR.