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Abstract SCLC is a lethal form of lung cancer and highly metastatic disease with limited therapeutic options. Four main neuro and non-neuroendocrine SCLC molecular subtypes have been identified which further complicate the efforts of finding targeted therapies. NRF2 is a transcription factor that is known to protect cells from oxidative damage by regulating more than 500 cytoprotective genes. NRF2 is frequently mutated in non-small cell lung cancer (NSCLC), however, whether alterations occur in small cell lung cancer (SCLC) is not clear due to limited sequencing data. Recently, our group has discovered a previously unrecognized role of NRF2 signaling pathway in the development of SCLC using a novel genetically engineered mouse model (GEMM). In this study, we have investigated the role of NRF2 in the progression and regression of human SCLC. Human SCLC cell lines were generated with NRF2E79Q/+ mutation (one of the most common mutations found in human tumors) to allow the constitutive activation of NRF2 in these cells. Results from hSCLC cell lines showed that NRF2 activation in NRF2-negative SCLCs can significantly inhibit their growth. Further, human SCLC gene expression data showed reduced levels of a NRF2 signature as hSCLC neuroendocrine SCLC transforms to non-neuroendocrine subtypes. As an anti-inflammatory pathway, NRF2 is known to inhibit immune cell gene signature. Our in vivo and invitro studies showed that NRF2 inhibits immune cell infiltration in SCLC; and increases PDL1 protein expression. Currently, we are investigating the effect of NRF2 activation in hSCLC growth, neuroendocrine differentiation and immune gene activation in vitro and in vivo. We are also using immune checkpoint inhibitors to determine the best therapeutic options for each SCLC subtype. Citation Format: Samera Hamad, Hansa Joshi, Yahui Li, Helen Toma, Nasrine Bendjilali, Stuart Jefferys, David Corcoran, Weam Elbezanti, Ben Major, Weissman Bernard, Francis Spitz. Neuroendocrine differentiation and treatment of human SCLC: NRF2 has a role 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 (6Suppl): Abstract nr 3842.
Hamad et al. (Fri,) studied this question.