Abstract 1496: Paired, single-cell profiling of circulating tumor cell-derived xenograft models of small cell lung cancer reveals intratumoral heterogeneity and emergence of new cell clusters following treatment relapse

Small cell lung cancer (SCLC), the most aggressive form of lung cancer, is notable for early dissemination and impressive, yet transient, responses to frontline chemotherapy that are rapidly undone by refractory relapses. To gain a better understanding of resistance mechanisms, we generated circulating tumor cell-derived xenograft (CDX) models from liquid biopsies of SCLC patients and treated them with chemotherapy or targeted agents. As expected, CDXs demonstrate similar chemotherapy response to the patient from whom they were derived. We have previously established that baseline chemosensitive CDXs are molecularly homogeneous at the single cell level, while chemoresistant CDXs exhibit increased intratumoral heterogeneity (ITH) with distinct variations in gene expression between cancer cell populations. We hypothesize that paired analyses of chemosensitive CDXs will demonstrate increased ITH after developing acquired resistance and are likely to offer more specific insights into resistance mechanisms than prior work with unrelated CDX models. Platinum-sensitive CDXs were treated with cisplatin or DNA damage response targeted therapies (PARP inhibitor or CHK inhibitor) continuously until tumor progression was observed. To identify transcriptional changes associated with onset of resistance, single-cell RNAseq analysis was performed on vehicle-treated and relapsed CDX tumors. We found globally increased ITH including heterogeneous expression of therapeutic targets and potential resistance pathways, such as EMT, between cellular subpopulations following treatment-resistance. Relapse was consistently associated with increased ITH score (P