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

Nasha Zhang1, Yankang Li2, Mengyu Xie2

  • 1Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China; Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China; Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China.

Biochemical Pharmacology
|December 24, 2019
PubMed

Insights

A specific gene variant (rs9364433) in DACT2 influences gene expression and gefitinib sensitivity in non-small cell lung cancer (NSCLC) patients, impacting treatment outcomes.

Area of Science:

  • Genetics
  • Oncology
  • Molecular Biology

Background:

  • Epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer (NSCLC) patients benefit from EGFR-tyrosine kinase inhibitor (TKI) therapy.
  • Drug resistance to EGFR-TKIs presents a significant clinical challenge.
  • Single nucleotide polymorphisms (SNPs) may influence the prognosis of EGFR-TKI therapy.

Purpose of the Study:

  • To investigate the functional SNP (rs9364433) in DACT2, a Wnt/β-catenin signaling inhibitor, and its impact on gene expression and prognosis in EGFR-TKI treated NSCLC patients.
  • To evaluate the allele-specific regulation of DACT2 expression by rs9364433 and its effect on gefitinib sensitivity.

Main Methods:

  • Genotyping of the DACT2 promoter rs9364433 SNP in two independent cohorts of 319 EGFR-TKI treated stage IIIB/IV NSCLC patients.
  • In vitro and in vivo evaluation of allele-specific DACT2 expression regulation and gefitinib sensitivity.
  • Reporter gene assays and Electrophoretic Mobility Shift Assays to determine the mechanism of SNP action.

Main Results:

  • Cox regression analyses revealed a significant association between rs9364433 and patient survival in both cohorts (P < 0.05).
  • The rs9364433 SNP demonstrated allele-specific effects on DACT2 expression, modulated by transcription factor TFAP2A.
  • The G allele of rs9364433 resulted in decreased DACT2 expression and enhanced gefitinib sensitivity in NSCLC cells.

Conclusions:

  • The DACT2 rs9364433 SNP significantly impacts gene expression and gefitinib sensitivity in NSCLC.
  • This SNP may serve as a predictive biomarker for EGFR-TKI treatment outcomes.
  • Understanding the role of DACT2 and its genetic variations can improve treatment strategies and outcome assessment for NSCLC patients.
Keywords:
DACT2EGFR-TKIsGenetic polymorphismLung adenocarcinomaTFAP2A

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