FOXA1 drives chemoresistance through activating Wnt pathway in small cell lung cancer

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor. While chemotherapy has been the cornerstone of first-line treatment, most SCLC patients develop chemoresistance shortly after an initial response, and the molecular basis of this resistance remains poorly understood. This study aims to identify novel drivers of SCLC chemoresistance.

FOXA1 copy number alterations and expression patterns were analyzed using public databases and validated by immunoblotting and immunohistochemistry. The functional role of FOXA1 in chemoresistance was determined through in vitro and in vivo gain- and loss-of-function assays. RNA sequencing and chromatin immunoprecipitation sequencing were performed to investigate underlying mechanisms. The functional significance of FOXA1-WNT5A-Wnt axis was tested using genetic perturbations and pharmacological inhibition.

FOXA1 was a frequently amplified and upregulated gene in SCLC. FOXA1 overexpression promoted resistance to chemotherapy. Mechanistically, WNT5A was identified as a direct downstream target of FOXA1, mediating chemoresistance through activation of the Wnt/β-catenin pathway. FOXA1 also induced epithelial-mesenchymal transition (EMT) in SCLC cells. Consistently, human SCLC tumors with elevated FOXA1 expression exhibited enriched EMT and Wnt/β-catenin pathway signatures. Importantly, pharmacological inhibition of the Wnt pathway selectively suppressed the growth of FOXA1-overexpressing SCLC cells.

This study identifies FOXA1 as a key driver of chemoresistance in SCLC and highlights Wnt pathway inhibition as a promising therapeutic strategy to overcome FOXA1-driven chemoresistance.