Abstract 1687: Estrogen-related receptor gamma (ERRγ) as a therapeutic target and the synergetic anti-tumor effect of DN200434 (ERRγ inverse-agonist) and MK2206 (Akt inhibitor) in non-small cell lung carcinoma (NSCLC)

Abstract Introduction: Non-small cell lung cancer (NSCLC) accounts for over 85% of all lung cancer cases and has the greatest mortality rates among both men and women, making it the primary cause of cancer-related fatalities globally. Estrogen Related Receptor Gamma (ERRγ), a member of the NR3B nuclear receptor subfamily, holds therapeutic promise in various cancer treatments. This study delves into the mechanistic understanding of ERRγ expression in NSCLC cells to gauge its therapeutic potential and examine the anti-tumor impact of combining DN200434 (ERRγ inverse agonist) with MK2206 (Akt inhibitor) in vitro. Experimental procedures: Expression of ERRγ were investigated in different NSCLC cell lines (A-549, H-1299, H-460) by western blot. Different dose of DN200434 was treatment to study the proliferation effect in NSCLC cells. CCK-assay was used to measure the IC50 value post DN200434 or/and MK2206 in NSCLC cells after 24 hours. NSCLC cells were treated with single drug or in combination to assess their inhibitory effect, apoptosis, cell cycle arrest, colony formation efficiency, migration potential, and spheroid forming ability and the markers of the corresponding events was validated by western blot. Summary of unpublished findings (Results): ERRγ was found to be overexpressed in the NSCLC cells. Treatment of DN200434 in NSCLC cells inhibit cell proliferation via apoptosis and cell cycle arrest in dose dependent manner. DN200434 in combination with MK-2206 demonstrate synergetic killing effect in NSCLC cells. Combination treatment inhibits cell proliferation via apoptosis and cell cycle-arrest, colony formation efficiency, migration potential, and sphere forming ability of NSCLC cells. This combination not only reduced the toxic concentration of both the drug but also target multiple key driving factors of NSCLC progression. Further, DN200434/MK-2206 reduced the stemness property of NSCLC cell-derived spheroids. Conclusions: Our present findings thus demonstrate that ERRγ functions as a positive regulator of NSCLC progression and a potential therapeutic target. DN200434, inverse agonist of ERRγ, along with MK-2206 suppresses cancer growth and represses the expression of ERRγ mediated signalling. This combination is certainly providing a new strategy to proceed towards clinical trial. Citation Format: Thoudam Debraj Singh. Estrogen-related receptor gamma (ERRγ) as a therapeutic target and the synergetic anti-tumor effect of DN200434 (ERRγ inverse-agonist) and MK2206 (Akt inhibitor) in non-small cell lung carcinoma (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1687.