Abstract
Growth arrest-specific 6 (Gas6) has been implicated in carcinogenesis through activation of its receptors, particularly MerTK. To investigate whether Gas6 plays a role in resistance to NF-κB inhibitors, which have not proven to be effective agents for lung cancer therapy, we studied lung cancer models induced by urethane injection or expression of mutant Kras (KrasG12D). We found that Gas6 is primarily produced by macrophages during tumorigenesis and that Gas6 is negatively regulated by NF-κB. Since Gas6 is a vitamin K dependent protein, we used low-dose warfarin to block Gas6 production and showed that this treatment inhibited tumorigenesis in both the urethane and KrasG12D models, most prominently in mice with targeted deletion of IKKβ in myeloid cells (IKKβΔMye mice). In addition, MerTK deficient mice had reduced urethane-induced tumorigenesis. Inhibition of the Gas6-MerTK pathway in all these models reduced macrophages and neutrophils in the lungs of tumor-bearing mice. Analysis of mouse lung tumors revealed MerTK staining on tumor cells and in vitro studies showed that Gas6 increased proliferation of human lung cancer cell lines. To assess the therapeutic potential for combination treatment targeting NF-κB and Gas6-MerTK, we injected Lewis Lung Carcinoma cells subcutaneously and treated mice with Bay 11-70852 (NF-κB inhibitor) and/or Foretinib (MerTK inhibitor). While individual treatments were ineffective, combination therapy markedly reduced tumor growth, blocked tumor cell proliferation, reduced tumor-associated macrophages, and increased CD4+ T cells. Together, our studies unmask a role for Gas6-MerTK signaling in lung carcinogenesis and indicate that up-regulation of Gas6 production in macrophages could be a major mechanism of resistance to NF-κB inhibitors.
Highlights
Lung cancer is the leading cause of cancer death in the United States [1]
To investigate whether Growth arrest-specific 6 (Gas6) plays a role in resistance to NF-κB inhibitors, which have not proven to be effective agents for lung cancer therapy, we studied lung cancer models induced by urethane injection or expression of mutant Kras (KrasG12D)
We investigated whether lung macrophages express Gas6 during lung tumorigenesis
Summary
Lung cancer is the leading cause of cancer death in the United States [1]. Among the inflammatory cell types infiltrating the lungs during carcinogenesis, macrophages are the most heterogeneous, displaying phenotypic plasticity depending on the microenvironment. Inhibition of NF-κB in airway epithelial cells significantly reduces lung tumorigenesis in mice [9,10,11,12]. Consistent with a critical role for epithelial NF-κB in lung tumorigenesis, we showed that transgenic mice with inducible expression of a constitutively active form of IKKβ develop 3-4-fold more lung tumors after carcinogen treatment [13]. These data point to NF-κB inhibition as a potentially effective strategy for prevention or treatment of lung cancer. Consistent with this report, we showed that prolonged NF-κB inhibitor treatment in mice resulted in increased lung tumor formation after treatment with urethane [15]
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