163P Integrative analysis of small cell lung cancer patient-derived xenograft models reveals subtype-specific pathway alterations and therapeutic targets

Small cell lung cancer (SCLC) accounts for 14% of diagnoses and is characterized by rapid onset chemoresistance poor clinical outcomes. SCLC has four major subtypes driven transcription factors ASCL1, NEUROD1, POU2F3, YAP1. Recent studies have also shown intratumoral heterogeneity with respect to ASCL1/NEUROD1 balance MYC amplification – which are potential mechanisms underlying SCLC’s aggressive refractory biology. Unfortunately, patient-derived models better characterize the molecular profiles scarce. We generated 46 (PDX)/circulating tumor cell-derived xenograft (CDX) derived from 33 patients treatment-naïve or relapsed SCLC. performed multi-omic analyses deconvolute mutational landscapes, global expression profiles, these models. Our revealed mutations typical (e.g. TP53, RB1), were maintained in vivo over multiple passages. Consistent known distribution subtypes, most our samples express ASCL1 both NEUROD1. looked into an inflamed gene signature, including immune checkpoint genes human leukocyte antigens (HLAs). Seven showed high HLAs related antigen presentation such as HLA-DRA HLA-DBP1. To date, there no reports animal model representing POU2F3 subtype. cohort included 10 POU2F3-driven primary metastatic tumors a patient ES-SCLC. These novel include IHC RNA-seq; low neuroendocrine (NE) markers; notably mitochondrial MT-RNR2 MT-CO3/1; REST BACH2; DLL3 ATOH1; metabolic comparison non-SCLC-P ABCB6, PGD, G6PD, highlighting samples. PDX/CDX characterization provide unique system resource biology inform research treatment strategies