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Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
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β-catenin/TCF activity regulates IGF-1R tyrosine kinase inhibitor sensitivity in colon cancer

Hani Lee1,2, Nayoung Kim2,3, Young Ji Yoo1,2

  • 1Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.

Oncogene
|June 14, 2018
PubMed

Insights

Transcriptional activity of β-catenin/TCF responsive promoters is a strong predictor of insulin-like growth factor 1 receptor/Insulin Receptor (IGF-1R/IR) tyrosine kinase inhibitor (TKI) response in colon cancer. This finding offers a more reliable biomarker than gene mutations for targeted therapy efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacogenomics

Background:

  • Large-scale drug screening data offers opportunities to discover predictive biomarkers for targeted drug efficacy.
  • Insulin-like growth factor 1 receptor/Insulin Receptor (IGF-1R/IR) tyrosine kinase inhibitors (TKIs) show promise in colon cancer treatment.
  • Identifying reliable biomarkers is crucial for optimizing targeted therapy selection.

Purpose of the Study:

  • To identify predictive biomarkers for IGF-1R/IR TKI efficacy in colon cancer.
  • To investigate the association between β-catenin/TCF pathway activity and IGF-1R/IR TKI response.
  • To compare the predictive power of transcriptional activity versus gene mutational status.

Main Methods:

  • Analysis of large-scale drug screening data across ~990 cancer cell lines.
  • Assessment of β-catenin/TCF-responsive promoter activity and its correlation with drug sensitivity.
  • Experimental validation using CTNNB1 gain-of-function mutations in TKI-resistant cells.
  • Analysis of The Cancer Genome Atlas (TCGA) data for human colon cancer specimens.

Main Results:

  • Enhanced sensitivity to IGF-1R/IR TKIs was observed in colon cancer cells.
  • β-catenin/TCF promoter activity positively associated with IGF-1R/IR TKI response, unlike upstream gene mutations (CTNNB1, APC).
  • High β-catenin/TCF activity cell lines showed increased IGF-1R/IR signaling components, correlating with TKI sensitivity.
  • Experimental and TCGA data confirmed the association between β-catenin/TCF activity, IGF-1R/IGF2 expression, and TKI response.

Conclusions:

  • β-catenin/TCF responsive promoter activity is a stronger predictive biomarker for IGF-1R/IR TKI response in colon cancer than upstream gene mutational status.
  • Transcriptional activity holds potential as a therapeutic biomarker for targeted therapies, overcoming limitations of genetic mutation analysis.
  • This study emphasizes the clinical utility of transcriptional biomarkers in precision oncology.

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