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

Abstract

Abstract 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.