Abstract 436: NRF2 activity impairs the efficacy of sotorasib in human KRAS-mutant lung adenocarcinoma

Abstract Lung cancer continues to be the leading cause of cancer-related mortality in the United States, with lung adenocarcinoma (LUAD) representing the most common histological subtype. Clinical evidence has demonstrated that tumor plasticity—, the transformation between lung cancer subtypes—, plays a crucial role in the development of resistance to chemotherapy and targeted therapies. Hyperactivation of NRF2, a transcription factor that normally protects cells from oxidative damage, is implicated in the resistance to various types of therapies including chemotherapies and targeted therapies. This study aimed to identify if NRF2 induces the resistance to carboplatin, and/or to sotorasib, a targeted therapy of KRAS-mutant LUAD, through histological transformation. We used KRAS-mutant human lung adenocarcinoma cell lines, high NRF2WT-A549, and H358 with NRF2E79Q activating mutation. Our results show that treatment of high-NRF2 LUAD cell lines with sotorasib induces the transformation to neuroendocrine tumors (NE) and augments the NRF2 levels in vitro. Further, this transformation increased the growth and invasion of the transformed tumor cells. Interestingly, the low-NRF2 version of H358 (without NRF2E79Q activating mutation) did not have these changes. Further, LUAD cell lines had good responses to carboplatin with and without NRF2 activation. This NRF2-treatment interaction study shows that carboplatin might be a good option in NRF2-high LUAD with KRAS mutation and that targeting NRF2 in NRF2high LUAD tumors could enhance the efficacy of sotorasib and prevent the transformation after treatment. Current studies in our lab are testing these changes in vivo using immunodeficient mice. Citation Format: T Hess, Hansa Joshi, Yaas Azmoudeh, Gord Zhu, Francis Spitz, David Shersher, Samera Hamad. NRF2 activity impairs the efficacy of sotorasib in human KRAS-mutant lung adenocarcinoma [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 436.