Intratumoral heterogeneity predicts resistance in CTC-derived models of small cell lung cancer [RNA-Seq]

Small cell lung cancer (SCLC) is an aggressive malignancy characterized by rapid onset of resistance to platinum chemotherapy. However, the mechanisms underlying platinum-resistance remain obscure in part due to scarcity of tissue samples, particularly from relapsed patients. Here, we generated circulating tumor cell (CTC)-derived xenograft (CDX) models from SCLC patients before or after relapse that faithfully recapitulate patient tumor genomics and platinum response. Platinum-sensitive models were relatively homogeneous, whereas transcriptomic and proteomic analyses revealed enrichment of multiple targetable pathways and intertumoral heterogeneity among resistant models. Single-cell RNAseq profiling further identified greater intratumoral heterogeneity (ITH) associated with platinum-resistance. This included a population of DLL3low cells in resistant CDX models that demonstrated greater chemoresistance, suggesting that subtle shifts in the proportion of DLL3-expressing cells could impact response. Similarly, longitudinal single-cell transcriptional profiling of CTCs from patient blood reveals emergence of molecular markers of resistance and significantly greater ITH after disease relapse. Together, these data suggest that platinum-resistance involves a heterogeneous process of transcriptional fluidity with contributions from both preexisting cellular subpopulations and outgrowth of resistant populations, yielding a diverse cellular composition refractory to single-agent therapeutics. Overall design: small cell lung cancer CTC derived xenograft RNA-seq