Abstract Background: Lung cancer is the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) comprising 85% of cases and small cell lung cancer (SCLC) 15%. Tyrosine kinase inhibitors (TKIs) are the frontline therapy for EGFR-mutant and ALK-fusion adenocarcinomas, yet most patients develop resistance. In 5-10% of TKI-resistant cases, adenocarcinomas (ADC) undergo lineage switching to aggressive neuroendocrine (NE) carcinomas, including LCNEC and SCLC; these patients lack effective therapies and have poor clinical outcomes. To better study NE-transformed tumors, we established clinically relevant patient-derived xenograft (PDX) and xenograft-derived organoid (XDO) models to identify novel therapeutic vulnerabilities and elucidate mechanisms underlying NE transformation. Methods: Patient biopsy tissues were subcutaneously engrafted into NOD-SCID mice to generate nine NE-transformed PDX models, and six matched long-term XDOs (10 passages) were established using organoid culture protocol. PDXs/XDOs were characterized by H 1 μM). Preliminary high-throughput screening of XDOs with a 58-compound epigenetic probe library identified a candidate therapeutic target to be presented. Conclusion: Our NE-transformed models preserve patient tumor molecular features, histopathology, and therapeutic response, providing robust platforms to identify novel therapeutic strategies and dissect mechanisms driving lung NE transformation. Citation Format: Matthew Djan, Sebastiao N. Martins-Filho, Nhu-An Pham, Nikolina Radulovich, Quan Li, Ming Li, Geoffrey Liu, Ming Sound Tsao. Patient-derived tumor models of tyrosine kinase inhibitor-induced neuroendocrine-transformed lung carcinoma 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 3408.
Djan et al. (2026) studied this question.