DACT2 modulated by TFAP2A-mediated allelic transcription promotes EGFR-TKIs efficiency in advanced lung adenocarcinoma

Abstract Patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer (NSCLC) benefits from EGFR-tyrosine kinase inhibitor (TKI) treatment. However, drug resistance to EGFR-TKIs remains a great challenge. Single nucleotide polymorphisms (SNPs) may significantly influence prognosis of EGFR-TKI therapy. Herein, we hypothesized that the functional SNP in DACT2, coding a pivotal inhibitor of the Wnt/β-catenin signaling, may affect gene expression, which in turn, impact prognosis of NSCLC treated with EGFR-TKIs. Genotypes of the DACT2 promoter rs9364433 SNP were determined in two independent cohorts consisted of 319 EGFR-TKI treated stage IIIB/IV NSCLC patients. The allele-specific regulation on DACT2 expression by rs9364433 and impacts of DACT2 on gefitinib sensitivity was evaluated in vitro and in vivo. Cox regression analyses demonstrated that rs9364433 was significantly associated with patient survival in both cohorts (all P