Abstract 6797: Basal-state origins and genotype-specific trajectories of neuroendocrine plasticity in lung cancer

Abstract Neuroendocrine (NE) lineage plasticity is a unifying mechanism of therapeutic resistance across lung cancers, enabling adenocarcinomas (LUAD) to evade targeted therapies (e.g. EGFR, KRAS) and adopt high-grade NE histologies, including small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC). The conserved early states and genotype-specific trajectories driving NE plasticity remain unclear.We integrated targeted DNA sequencing, 10X single-cell transcriptomics (75 samples, 52 patients), and Xenium spatial imaging (22 samples, 16 patients) across NE-transformed lung cancers. Both EGFR-mutant (mut) and -wildtype (wt) transformed SCLC showed recurrent chromosomal instability and PI3K/AKT activating mutations. EGFR-mut cases were enriched for RB1 loss, whereas EGFR-wt had more CDKN2A loss as well as KRAS, STK11, and KEAP1 mutations. Single-cell data showed greater NE subtype diversity in transformed versus de novo NE cancers as well as dynamic transitions between NE and non-NE states. Our computational approaches (scDeBussy pseudotime alignment, factor analysis) converged on a conserved basal-like precursor enriched for JAK/STAT and NF-κB signaling that seeds multiple terminal outcomes, including NE, squamous, and mesenchymal fates. To identify regulators of the basal-to-SCLC transition, we compared transformed and de novo SCLC and found PHOX2Bas the transcription factor most correlated with NE state. PHOX2B overexpression in EGFR-mut LUAD cells with TP53/RB1 co-mutations induced NE markers, amplified by MYC activation and REST suppression. Although insufficient for full SCLC morphology, PHOX2B suppressed MAPK signaling (ERK/pERK), consistent with plasticity promoting EGFR independence. Recognizing STK11/KEAP1 co-mutations as an alternate route to NE plasticity, we analyzed NE tumors with these mutations. LCNEC showed highest frequency of STK11 and KEAP1 loss (28-31%) exceeding LUAD or SCLC (10-11%, 1-4%). Regulatory network analysis in LCNEC found a FOXA2-HNF1/4A axis reactivating a hepatic developmental program alongside NRF2-aldoketoreductase (AKR)-driven redox adaptation. Spatial imaging uncovered intratumoral zonation of immune-hot and -cold NE states, shaped by immunosuppressive cell-cell interactions (FGL1-LAG3, VEGFA-VEGFR).Together, these studies delineate a shared basal precursor to NE plasticity with later divergence shaped by genotype. PHOX2B represents a late molecular event inducing early NE induction and MAPK bypass in EGFR-mut tumors, while STK11/KEAP1-mut LCNEC coopts a distinct hepatic-NE program linked to metabolic and immune remodeling. This framework reveals biomarkers and vulnerabilities across early and late stages of LUAD-to-NE transformation, including inflammatory precursors, signaling bypass, metabolic rewiring, and immune evasion, offering multiple points for intervention across NE lung cancers. Citation Format: Meng Wang, Amin Sabet, Swanand Rakhade, Emmanuel Spanos, Lena Morrill Gavarró, Rishika Giri, Parvathy Manoj, Helena A. Yu, Alvaro Quintanal-Villalonga, John Thomas Poirier, Esther Redin, Dana Pe'er, Charles M. Rudin, Joseph M. Chan. Basal-state origins and genotype-specific trajectories of neuroendocrine plasticity in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6797.