Abstract 2931: AXL-directed surface targeting approaches in recalcitrant pulmonary high-grade neuroendocrine carcinomas

High-grade neuroendocrine carcinomas of the lung (hgNECs), which include small cell lung cancer (SCLC) and pulmonary large-cell neuroendocrine carcinoma (LCNEC), are characterized by poor prognoses, limited treatment options and rapid emergence of resistance. While recent surfaceome-directed approaches targeting DLL3, SEZ6, and TROP2 using chimeric antigen receptor T cells (CAR-Ts), bispecific T cell engagers (BiTEs) and antibody drug conjugates (ADCs) show considerable promise in hgNECs, novel strategies to target the heterogenous resistant disease are needed. AXL, a TAM family receptor tyrosine kinase, is known to mediate resistance to chemotherapy, radiation and targeted therapies in SCLC and other cancers, through its roles in epithelial to mesenchymal transition (EMT), DNA damage repair and replication stress tolerance. We hypothesize that targeting cell surface AXL would provide an effective therapeutic strategy in hgNECs, especially for relapsed disease. We analyzed the transcriptomic (bulk and single-cell RNA sequencing) and proteomic (immunohistochemistry) expression profiles of AXL in treatment-naïve and relapsed SCLC, LCNEC and other extrapulmonary hgNECs patient tumors. High levels of AXL expression were seen in distinct tumor subsets. Notably, AXL-high tumors exhibited molecular signatures associated with resistance (higher EMT scores, lower replication stress and cisplatin response). To evaluate AXL as a viable surface target in hgNECs, we generated a preclinical CAR T cell against AXL. Anti-AXL CAR T cells were effective at inducing cytotoxicity in AXL-expressing SCLC and LCNEC cell lines. Similarly, an anti-AXL ADC also showed selective and potent cytotoxicity in AXL-positive models. These findings establish AXL as both a valuable biomarker and a promising target for the drug-resistant hgNECs, supporting the development of AXL-directed therapeutics such as anti-AXL CAR T cells and anti-AXL ADCs. Citation Format: Kavya Ramkumar, C. Allison Stewart, Yan Yang, Bingnan Zhang, Qi Wang, Yuanxin Xi, Runsheng Wang, Alejandra G. Serrano, Luisa M. Solis Soto, Jing Wang, John V. Heymach, Carl M. Gay, Lauren A. Byers. AXL-directed surface targeting approaches in recalcitrant pulmonary high-grade neuroendocrine carcinomas [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 2931.