Shengxiang Ren

Abstract Although third-generation Epidermal growth factor receptor—tyrosine kinase inhibitors (EGFR-TKI) is standard of care for patients with EGFR-mutant Non-small cell lung cancer (NSCLC), little is known about the predictors of response or resistance. Here, we integrated single-cell RNA (scRNA) sequencing, bulk RNA sequencing, multiplexed immunofluorescence and flow cytometry data from pretreatment and post-resistant tumor samples of EGFR-mutant NSCLC patients received third-generation EGFR-TKIs. We show that resistant samples had a markedly enriched CXCR1 + neutrophils infiltration ( P < 0.01) than pretreatment samples, which were distinguished from other subtypes of neutrophils and displayed immunosupressive characteristics. Spatial analysis showed that increased CXCR1 + neutrophils predominantly infiltrated into the tumor core in resistant samples and the average distance of neutrophils to tumor cells markedly reduced from 33 to 19 μm. Deep analysis of scRNA and bulk RNA sequencing data revealed the increased interactions between CXCR1 + neutrophils and tumor cells and activated TNF-α/NF-κB signaling pathway in tumor cells of resistant samples. In vitro and in vivo experiments validated that CXCR1 + neutrophils resulted in resistance to third-generation EGFR-TKI via activating TNF-α/NF-κB signaling pathway in tumor cells. Importantly, patients with low pretreatment CXCR1 + neutrophil infiltration abundance had a dramatically longer progression-free survival (11.8 vs. 7.5 months; P = 0.019) and overall survival (33.0 vs. 23.5 months; P = 0.029) than those with high infiltration abundance. Collectively, these findings suggest that CXCR1 + neutrophils infiltration was associated with the efficacy of third-generation EGFR-TKI in patients with EGFR-mutant NSCLC.

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.

The discovery of anaplastic lymphoma kinase (ALK) tyrosine kinase gene rearrangement mutations in non-small cell lung cancer (NSCLC) has driven continuous advancements in ALK-targeted therapies. The next generation of ALK tyrosine kinase inhibitor, Brigatinib, has demonstrated significant efficacy in patients with ALK-positive NSCLC, offering clinical benefits in deep response of tumor, treatment of brain metastases patients, quality of life, and long-term survival. This review will provide current advancements and exploratory directions for Brigatinib. .