YAP1 Defines an Emergent, Plastic Population of Relapsed SCLC

INTRODUCTION: SCLC is an aggressive neuroendocrine malignancy characterized by rapid onset of chemoresistance and poor clinical outcomes. Transcriptional heterogeneity among treatment-naive SCLC tumors underlies four transcriptional subtypes, each with distinct clinical vulnerabilities. Though previously hypothesized to delineate a distinct subtype, expression of YAP1 is largely absent from treatment-naive, pure SCLC. METHODS: Methods: To characterize relapsed SCLC, circulating tumor DNA, circulating tumor cells, and core needle biopsies from patients with SCLC and preclinical models following resistance to standard-of-care therapies were analyzed. RESULTS: In contrast to treatment-naive SCLC, these analyses reveal an emergent YAP1-positive cell population that coincides with treatment resistance. These YAP1-positive cells exhibit characteristics of drug-tolerant persister cells, including senescence, stemness, and plasticity, as YAP1-positive cells largely abandon features characteristic of SCLC to adopt those of large cell neuroendocrine carcinoma. As a result of this SCLC-like to large cell neuroendocrine carcinoma-like evolution, YAP1-positive cells lack several clinically relevant SCLC surface targets (i.e., DLL3, SEZ6) but are enriched for others (i.e., B7-H3, TROP2) CONCLUSIONS: We propose a model where YAP1-expressing cells emerge with SCLC treatment resistance and characterize a tenacious subpopulation capable of diverging from the treatment-naive lineage and adopting features to evade therapeutic response.