Abstract 4885: Targeting heterogeneity to improve non-small cell lung cancer treatments

Abstract Non-small cell lung cancer (NSCLC) is currently the leading cause of cancer related death in the United States. Despite improvements in treatment, success is extremely varied due to tumor heterogeneity. Our laboratory hypothesis that targeting heterogeneity could improve treatment responses for NSCLCs. Our first method to accomplish this is to inhibit the histone methyltransferase EZH2, which tri-methylates histone 3 lysine 27 to silence genes. Using a syngeneic lung cancer model, we observed that the EZH2 inhibitor valemetostat combined with anti-PD1 immunotherapy drives tumor regression, increased activated T cells and increased antigen expression on the tumor cells. This switch to an MHC class II high state makes the tumors susceptible to immunotherapy-mediated cell killing. To closely study tumor-immune cell interactions ex vivo, our lab has optimized 3D tumoroid model that recapitulates the liquid air interface seen within the lung and immune cells. With this model, we have observed that bone marrow from valemetostat-treated mice led to a depletion of tumoroids, and an increase in CD8+ T cells. In addition to EZH2 inhibition that is currently in clinical trial, we are also exploring methionine restriction (MR) as an alternative way to alter heterogeneity. Methionine is a pre-cursor to S-adenosyl methionine, the methyl donor for EZH2. Our previous studies showed that dietary MR improved carboplatin response and slowed tumor progression in an aggressive KRAS/Lkb1 mouse model1. Given some controversy around MR and immunotherapy, we next performed a syngeneic graft assay with the mixed lineage KRAS/Lkb1 tumor cells. We observed that MR coupled with carboplatin and or anti-PD1 lead to improved response compared to control arms. We have also created “multi-culture” experiments that mirror the dietary intervention approach by reducing methionine within the media and treating with chemotherapy + anti-PD1. We observed that tumoroid growth in low methionine was stalled, particularly for KRAS/Lkb1 tumoroids co-treated with chemo + anti-PD1. We also show that with the low methionine media there were significantly more T-cells present. Together these studies show that modulating EZH2 or methionine levels in NSCLC are effective ways to increase treatment efficacy. We also demonstrate use of cutting edge “multi-culture” experiments that can successfully model in vivo environments to better predict cancer response to treatment. 1 doi: https://doi.org/10.1101/2024.06.25.599795. This work was funded by: Markey STRONG Scholars Program through the American Cancer Society IRG-22-152-34 (HY), T32 CA165990 (DRP), R01 CA237643 (CFB), R01 HL170193 (CFB), P30 CA177558 (Markey Shared Resources) Citation Format: Avery Childress, Xiulong Song, Dave-Preston I. Esoe, Christian M. Gosser, Harrison Yang, Kassandra J. Naughton, Daniel R. Plaugher, Zhonglin Hao, Christine F. Brainson. Targeting heterogeneity to improve non-small cell lung cancer treatments [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 4885.