FOXM1 targeting alters AURKB activity and reshapes antitumor immunity to curb the progression of small cell lung cancer

Small cell lung cancer (SCLC) is a lethal lung malignancy which is associated with distant metastasis and chemoresistance. Limited targeted therapies further worsen disease outcomes. Single-cell and bulk RNA-sequencing (RNA-seq) datasets were analyzed that revealed FOXM1 as a potential targeting candidate in SCLC. High FOXM1 expression in human and murine SCLC tissues and cell lines was observed. Interestingly, chemoresistant (CR) SCLC cells exhibited substantially higher FOXM1 expression compared to naïve SCLC. Furthermore, FOXM1 inhibition in combination with platinum-based chemotherapy showed synergistic anticancer effects in vitro and in vivo xenograft and spontaneous (RPM: RB1 ^fl/fl ; TP53 ^fl/fl ; LSL-MYCT58A) mouse models of SCLC. Mechanistically, RNA-seq analysis revealed that FOXM1 inhibition altered the Aurora Kinase B (AURKB) signaling pathway. Notably, FOXM1 inhibition enhanced T cell activation, supported differentiation of CD8+ T cells, and T cell-mediated killing of cancer cells. Additionally, FOXM1 inhibition enhanced CD8+ T cell and macrophage recruitment in the TME of immunocompetent RPM model. This study demonstrates that FOXM1 targeting small molecule inhibitors (FOXM1i) has the potential to be a novel therapeutic strategy to combat SCLC progression, including chemotherapeutic resistance and reshaping the anti-tumor immune response.