Abstract 2028: The triterpenoid CDDO-Methyl ester requires Nrf2 to decrease lung tumor burden and to protect against the toxicity of chemotherapy in experimental lung cancer
Authors: Moerland Jessica Ann , Liby Karen T. 
Published: March 2024

Abstract
The NRF2 cytoprotective pathway, a drug target for many inflammation-related diseases, regulates immune cell function. While the anti-inflammatory nature of NRF2 activation protects healthy cells from malignant transformation, cancer cells can utilize the pathway to promote resistance to anti-cancer drugs. Up to 30% of human lung adenocarcinomas acquire mutations in either NFE2L2 or its negative regulator KEAP1 which result in constitutive activation of the NRF2 pathway. However, despite our knowledge of the important immunomodulatory effects of NRF2, these effects are not well characterized in the context of cancer. With NRF2 activators now approved for clinical use, it is critical to understand the impact of these drugs in cancer. Triterpenoids including CDDO-methyl ester (CDDO-Me, also known as bardoxolone methyl) are potent pharmacological NRF2 activators with demonstrated anti-cancer activity in preclinical models. In an early-stage preclinical model of lung cancer, CDDO-Me significantly decreased tumor burden in a dose- and Nrf2-dependent manner and improved immune signatures within the tumor microenvironment. However, most human lung cancers are not diagnosed until more advanced stages. To test CDDO-Me in an established tumor intervention model, lung tumors were initiated with vinyl carbamate in A/J WT and Nrf2 knockout (KO) mice. Tumors were allowed to develop for 8 weeks post initiation, after which mice were fed either a vehicle control diet or CDDO-Me (50-100 mg/kg of diet) for an additional 8-12 weeks, alone or in combination with carboplatin and paclitaxel (C/P) at 50 mg/kg and 15 mg/kg, respectively, by IP injection every other week. CDDO-Me significantly (p &lt; 0.05) decreased surface lung tumor counts 35-71% in a Nrf2-dependent manner, and C/P significantly (p &lt; 0.001) reduced tumor burden 53-59% regardless of Nrf2 status. The combination of CDDO-Me + C/P reduced tumor burden in WT lungs by 84% (p &lt; 0.05), more than either agent alone. Nrf2 KO mice had an approximately two-fold increase (p &lt; 0.001) of surface tumors compared to WT mice in both studies, regardless of treatment. C/P reduced tumor burden similarly in Nrf2 WT and Nrf2 KO mice. Interestingly, the combination of CDDO-Me + C/P increased T cell infiltration into the lungs of WT mice, but this change was not observed in groups treated with either agent alone. Importantly, CDDO-Me did not decrease the efficacy of C/P but protected WT mice from mortality and weight loss and lowered white and red blood cell counts. These studies suggest that NRF2 activation in advanced lung cancers can still decrease tumor burden by favorably modulating the immune microenvironment and, importantly, complements the anti-tumor efficacy of conventional chemotherapy while decreasing drug toxicity.
Citation Format: Jessica Ann Moerland, Karen T. Liby. The triterpenoid CDDO-Methyl ester requires Nrf2 to decrease lung tumor burden and to protect against the toxicity of chemotherapy in experimental lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2028.