Abstract 1335: The ubiquitin E3 ligase SCFSkk2/Cks1complex: A critical node coupling cell cycle control, tumorigenesis, and lineage fidelity in small cell lung cancer (SCLC).

Abstract Background: Mutation and inactivation of RB1 and TP53 are required and sufficient to drive small cell lung cancer (SCLC) tumorigenesis, both clinically and in mouse genetic models. We previously reported that the knockout of the Skp2 component of the ubiquitin E3 ligase SCFSkp2/Cks1 protected Rb1/Trp53-deficient mice from SCLC tumorigenesis but also increased the frequency of lung tumors with non-SCLC phenotypes. To explore this observation, we used a SCLC mouse model in which tumorigenesis was induced by CGRP-Cre-mediated deletions of Rb1, Trp53, and Pten (RPPt) in the neuroendocrine cells of the lungs. We crossed these to mice with either Skp2 knockout or the knockin (KI) of a mutated, inactivated SCFSkp2 accessory protein, Cks1 (Cks1N45R), that prevents the binding of p27 to SCFSkp2. Methods: We generated mouse lung cancer models using neuroendocrine cell-specific Rb1; Trp53; Pten triple-knockout mice with Skp2-KO or with Cks1N45R KI. Tumorigenesis, survival, and metastasis were monitored. Lung tumors were analyzed for neuroendocrine, SCLC subtype, squamous and other markers. Primary cell lines were established from lung tumors and characterized for lineage fidelity and sensitivity to cytotoxic and targeted drugs in vitro and in vivo. Results: Skp2 mRNA was elevated in human SCLC cell lines and PDXs. In RPPt mice, both Skp2-KO and Cks1N45R KI reduced lung tumor and liver metastasis incidence, increased survival, and caused a striking phenotypic shift. RPPt mouse tumors were SCLC with neuroendocrine staining. In contrast, tumors in both Skp2-KO and Cks1N45R KI mice lacked neuroendocrine markers and had squamous cell histology with staining for Sox2, KRT5, and p63. RPPt lung tumors were ASCL1+ and YAP1-. Conversely, the Skp2-inactivated tumors were ASCL1- and YAP1+ and retained SMARCA4 expression. Cell lines derived from the RPPt lung tumors grew more rapidly and were more sensitive to cisplatin and etoposide than were the lung tumor cells from the RPPt-Cks1N45R KI mice. The RPPt lung tumor cells were also more sensitive to growth inhibition by the SCFSkp2/Cks1 inhibitors C1 and pevonedistat and the CDK1/2/5/9 inhibitor dinaciclib. Finally, pevonedistat inhibited RPPt tumor growth in vivo. Conclusion: These findings are consistent with the hypothesis that the Rb1/Trp53-deficient SCLC neuroendocrine phenotype is not a fixed feature but can vary with the presence of other oncogenic drivers, and document SCFSkp2/Cks1 as one such driver. This could reflect an early, deterministic lineage redirection toward a YAP1-high, SMARCA4-intact, non-neuroendocrine phenotype. SCFSkp2/Cks1 mediates lung cancer heterogeneity, plasticity and sensitivity to standard cytotoxic and targeted drugs. Furthermore, the in vivo efficacy of the neddylation inhibitor pevonedistat highlights SCFSkp2 complex assembly as a promising therapeutic target for SCLC. Citation Format: Saumen Karan, Hongling Zhao, Yingjiao Xue, Xinrui Zhang, Bang Hoang, Luc Girard, Benjamin Drapkin, John D. Minna, Edward L. Schwartz. The ubiquitin E3 ligase SCFSkk2/Cks1complex: A critical node coupling cell cycle control, tumorigenesis, and lineage fidelity in small cell lung cancer (SCLC) 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 1335.