Differential expression of the MYC-Notch axis drives divergent responses to the front-line therapy in central and peripheral extensive-stage small-cell lung cancer

Central and peripheral extensive-stage small-cell lung cancer (ES-SCLC) are reported to be two distinct tumor entities, but their responses to the front-line therapies and underlying biological mechanisms remain elusive. In this study, we first compared the outcomes of central and peripheral ES-SCLC receiving front-line chemotherapy or chemo-immunotherapy with a cohort of 265 patients. Then we performed single-cell RNA sequencing (scRNA-seq) on nine treatment-naïve ES-SCLC samples to investigate potential mechanisms underlying the response differences. Under chemotherapy, the peripheral type had a lower objective response rate (44.8% vs. 71.2%, p = 0.008) and shorter progression-free survival (median 3.4 vs. 5.1 months, p = 0.001) than the central type. When comparing chemo-immunotherapy with chemotherapy, the peripheral type showed a greater potential to reduce progression (HR, 0.18 and 0.52, respectively) and death (HR, 0.44 and 0.91 respectively) risks than the central type. Concerning the scRNA-seq data, the peripheral type was associated with chemo-resistant and immune-responsive tumoral and microenvironmental features, including a higher expression level of MYC-Notch-non-neuroendocrine (MYC-Notch-non-NE) axis and a more potent antigen presentation and immune activation status. Our results revealed that central and peripheral ES-SCLC had distinct responses to front-line treatments, potentially due to differential activation statuses of the MYC-Notch-non-NE axis.