Lung cancer remains the leading cause of cancer-related mortality in the United States. While recent advances including immunotherapies and KRAS inhibitors have expanded therapeutic options and improved clinical management of lung cancer, significant challenges remain including limited patient response rates and the development of drug resistance. These obstacles necessitate the development of new treatments for lung cancer with increased efficacy and a broader target patient population. One strategy to achieve these goals is to develop drugs with wide-ranging effects on a variety of cellular processes. Such promiscuous mechanisms of action are particularly advantageous in conditions involving complex biological mechanisms such as cancer where targeting single pathways may be insufficient, as they can address multiple facets of the disease simultaneously. One such strategy is pharmacological activation of transcriptional systems, as the resulting widespread modulation of target gene expression can induce significant overhaul of major relevant cellular processes. This dissertation elucidates the anti-cancer effects of pharmacological activation of two different transcriptional programs: the Retinoid X Receptor (RXR), and the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. RXR is a ligand-dependent nuclear receptor which transcriptionally regulates many cancer-related cellular processes including development, differentiation, metabolism, and homeostasis. The novel RXR agonist MSU-42011 reduced tumor number, size, and burden in the A/J model of vinyl-carbamate induced lung cancer. Additionally, MSU-42011 in combination with carboplatin and paclitaxel (C/P) decreased pro-tumor macrophage CD206 expression and increased infiltration of activated anti-tumor CD8+ T cells. In comparison, the FDA-approved RXR agonist bexarotene did not reduce tumor burden in this model and no immunomodulatory effects were observed. The Nrf2 pathway is a master regulator of oxidative and electrophilic stressors resulting from accumulation of reactive oxygen species (ROS), hypoxia, pH changes, and other conditions common within the lung tumor microenvironment. While increased Nrf2 activity in tumor cells due to environmental conditions or mutations (e.g. Keap1 inactivation) promotes survival, the data presented in this dissertation show that pharmacological Nrf2 activation in the immune microenvironment promotes an anti-tumor phenotype which results in decreased lung tumor burden. The triterpenoid CDDO-Methyl Ester (CDDO-Me), a potent activator of Nrf2, reduces tumor number, size, and burden in a Nrf2-dependent manner. In WT mice, CDDO-Me decreased expression of the pro-tumor macrophage marker CD206 and the tumor-promoting Treg marker FoxP3 on CD4+ T cells while simultaneously increasing degranulation of activated CD8+ T cells. Strikingly, the anti-tumor effect of CDDO-Me + C/P was more effective than either agent alone in WT mice and CDDO-Me protected these mice from C/P-induced toxicity. Overall, pharmacological activation of the RXR and Nrf2 transcriptional systems reduce lung tumor burden and induce changes to the lung tumor microenvironment which shift this cell compartment from a tumor-promoting to a tumor-reducing phenotype. While transcriptional programs are incredibly complex pharmacological targets, this dissertation illustrates how powerful these systems can be in the treatment of complex diseases such as lung cancer.
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