The availability of large-scale drug screening data on cell line panels provides a unique opportunity to identify predictive biomarkers for targeted drug efficacy. Analysis of diverse drug data on ~990 cancer cell lines revealed enhanced sensitivity of insulin-like growth factor 1 receptor/ Insulin Receptor (IGF-1R/IR) tyrosine kinase inhibitors (TKIs) in colon cancer cells. Interestingly, β-catenin/TCF(T cell factor)-responsive promoter activity exhibited a significant positive association with IGF-1R/IR TKI response, while the mutational status of direct upstream genes, such as CTNNB1 and APC, was not significantly associated with the response. The β-catenin/TCF activity high cell lines express components of IGF-1R/IR signaling more than the low cell lines explaining their enhanced sensitivity against IGF-1R/IR TKI. Reinforcing β-catenin/TCF responsive promoter activity by introducing CTNNB1 gain-of-function mutations into IGF-1R/IR TKI-resistant cells increased the expression and activity of IGF-1R/IR signaling components and also sensitized the cells to IGF-1R/IR TKIs in vitro and in vivo. Analysis of TCGA data revealed that the stronger β-catenin/TCF responsive promoter activity was associated with higher IGF-1R and IGF2 transcription in human colon cancer specimens as well. Collectively, compared to the mutational status of upstream genes, β-catenin/TCF responsive promoter activity has potential to be a stronger predictive positive biomarker for IGF-1R/IR TKI responses in colon cancer cells. The present study highlights the potential of transcriptional activity as therapeutic biomarkers for targeted therapies, overcoming the limited ability of upstream genetic mutations to predict responses.
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Insulin-like growth factor receptor signaling in tumorigenesis and drug resistance: a challenge for cancer therapy
Journal of Hematology & Oncology Open Access 03 June 2020
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This work was supported by the National Research Foundation of Korea, [NRF-2018R1A2B6009313 to EJ], [NRF-2017R1A2B2007745, and NRF-2016R1A5A1011974 to SY] and [NRF-2012M3A9B6055466, NRF-2015R1D1A1A01056594, and NRF-2011-0030074 to W-YK].
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The authors declare that they have no conflict of interest.
These authors contributed equally: Hani Lee and Nayoung Kim
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Lee, H., Kim, N., Yoo, Y.J. et al. β-catenin/TCF activity regulates IGF-1R tyrosine kinase inhibitor sensitivity in colon cancer. Oncogene 37, 5466–5475 (2018). https://doi.org/10.1038/s41388-018-0362-5
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