Abstract 5864: YAP1 defines a highly plastic, persister cell population in small cell lung cancer (SCLC) following relapse

Abstract SCLC is an aggressive, neuroendocrine malignancy notable for rapid, albeit transient, responses to therapy. We have previously shown that transcriptional heterogeneity among treatment-naïve SCLC tumors underlies four distinct transcriptional subtypes, each with distinct clinical vulnerabilities. Though previously hypothesized to delineate a distinct subtype, expression of YAP1 is largely absent from treatment-naïve SCLC. Less clearly defined is the transcriptional landscape of relapsed SCLC, the evolution of which may underlie SCLC’s capacity for insurmountable resistance. To better define the biology of relapsed SCLC, we performed mass cytometry analysis of patient circulating tumor cells (CTCs), immunohistochemistry for ASCL1, NEUROD1, POU2F3, MYC and YAP1, and single-cell (sc)RNAseq of core needle biopsies from SCLC patients and preclinical models following resistance to standard-of-care therapies. In contrast to treatment-naïve SCLC, YAP1 mRNA and protein are detectable in patient CTC populations and tumors from relapsed patients and PDXs, albeit at levels lower than subtype-defining transcription factors (e.g. ASCL1, NEUROD1, or POU2F3). Notably, however, scRNAseq reveals these YAP1 expressing cells to be mutually exclusive with ASCL1 and NEUROD1, though not necessarily POU2F3. YAP1-expressing cells possess unique mesenchymal, inflamed features and exhibit high levels of transcriptional plasticity. Consistent with the upregulation of YAP1 following chemotherapy, YAP1-positive cell populations express senescence associated secretory phenotype genes and cancer stem cell genes, suggesting that these populations represent drug tolerant persister cells that may serve as a source for renewal of classical neuroendocrine populations within the tumor. Targeting these resistant populations may be critical to re-establish response in relapsed SCLC, and these analyses identified high expression of several surface proteins that are currently under investigation as targets for antibody-drug conjugates in SCLC clinical trials, including B7H3, TROP2 and HER2 antibody drug conjugates. These data suggest that the acquisition of YAP1 expression delineates a particularly recalcitrant tumor cell population observed almost exclusively in relapsed SCLC that is capable of driving tumor persistence and treatment resistance. Clinically, these data underscore the importance of constraining transcriptional plasticity in the frontline management of SCLC, but also of developing therapies aimed specifically at emergent populations capable of driving resistance, as with the YAP1-high cells identified here. The emergence of YAP1 following resistance in SCLC and the observation of YAP1 as a common feature of other high-grade neuroendocrine carcinomas exclusive of SCLC, likely explains the initial mischaracterization of YAP1 as a subtype-defining feature of SCLC. Citation Format: C. Allison Stewart, Sarah M. Groves, Runsheng Wang, Kavya Ramkumar, Yuanxin Xi, Lixia Diao, Alejandra G. Serrano, Azusa Tanimoto, Ashley M. Victorian, Sayantan Bhattacharyya, Alexa J. Halliday, Neda Kalhor, Luisa Maren Soto, Pedro Filipe Da Rocha, Natalie Vokes, Loukia G. Karacosta, Jing Wang, John V. Heymach, Vito Quaranta, Bonnie Glisson, Lauren Averett Byers, Carl M. Gay. YAP1 defines a highly plastic, persister cell population in small cell lung cancer (SCLC) following relapse [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(6_Suppl):Abstract nr 5864.