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β-catenin/TCF activity regulates IGF-1R tyrosine kinase inhibitor sensitivity in colon cancer

Oncogene volume 37, pages 5466–5475 (2018)Cite this article

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Abstract

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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Acknowledgements

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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Authors and Affiliations

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

    Hani Lee, Young Ji Yoo, Hyejin Kim, SeokGyeong Choi & Woo-Young Kim

  2. Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women’s University, Seoul, 04310, Republic of Korea

    Hani Lee, Nayoung Kim, Young Ji Yoo, Hyejin Kim, Euna Jeong, SeokGyeong Choi, Sung Un Moon, Sukjoon Yoon & Woo-Young Kim

  3. Department of Biological Sciences, Sookmyung Women’s University, Seoul, 04310, Republic of Korea

    Nayoung Kim & Sukjoon Yoon

  4. College of Pharmacy, Gachon University, Incheon, 21936, Republic of Korea

    Seung Hyun Oh

  5. Systems Biology, MD Anderson Cancer Center, University of Texas, Houston, TX, 77030, USA

    Gordon B. Mills

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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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