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

Hani Lee, Nayoung Kim, Young Ji Yoo, Hyejin Kim, Euna Jeong, Seok Gyeong Choi, Sung Un Moon, Seung Hyun Oh, Gordon Mills, Sukjoon Yoon, Woo Young Kim

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalOncogene
DOIs
StateAccepted/In press - Jun 12 2018
Externally publishedYes

Fingerprint

Somatomedin Receptors
Catenins
Protein-Tyrosine Kinases
Colonic Neoplasms
Cell Line
Biomarkers
Insulin Receptor
TCF Transcription Factors
Mutation
Preclinical Drug Evaluations
Pharmaceutical Preparations
Genes
insulin receptor tyrosine kinase

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Lee, H., Kim, N., Yoo, Y. J., Kim, H., Jeong, E., Choi, S. G., ... Kim, W. Y. (Accepted/In press). β-catenin/TCF activity regulates IGF-1R tyrosine kinase inhibitor sensitivity in colon cancer. Oncogene, 1-10. https://doi.org/10.1038/s41388-018-0362-5

β-catenin/TCF activity regulates IGF-1R tyrosine kinase inhibitor sensitivity in colon cancer. / Lee, Hani; Kim, Nayoung; Yoo, Young Ji; Kim, Hyejin; Jeong, Euna; Choi, Seok Gyeong; Moon, Sung Un; Oh, Seung Hyun; Mills, Gordon; Yoon, Sukjoon; Kim, Woo Young.

In: Oncogene, 12.06.2018, p. 1-10.

Research output: Contribution to journalArticle

Lee, H, Kim, N, Yoo, YJ, Kim, H, Jeong, E, Choi, SG, Moon, SU, Oh, SH, Mills, G, Yoon, S & Kim, WY 2018, 'β-catenin/TCF activity regulates IGF-1R tyrosine kinase inhibitor sensitivity in colon cancer', Oncogene, pp. 1-10. https://doi.org/10.1038/s41388-018-0362-5
Lee, Hani ; Kim, Nayoung ; Yoo, Young Ji ; Kim, Hyejin ; Jeong, Euna ; Choi, Seok Gyeong ; Moon, Sung Un ; Oh, Seung Hyun ; Mills, Gordon ; Yoon, Sukjoon ; Kim, Woo Young. / β-catenin/TCF activity regulates IGF-1R tyrosine kinase inhibitor sensitivity in colon cancer. In: Oncogene. 2018 ; pp. 1-10.
@article{d166638daf3046c6a254a12ce519001f,
title = "β-catenin/TCF activity regulates IGF-1R tyrosine kinase inhibitor sensitivity in colon cancer",
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.",
author = "Hani Lee and Nayoung Kim and Yoo, {Young Ji} and Hyejin Kim and Euna Jeong and Choi, {Seok Gyeong} and Moon, {Sung Un} and Oh, {Seung Hyun} and Gordon Mills and Sukjoon Yoon and Kim, {Woo Young}",
year = "2018",
month = "6",
day = "12",
doi = "10.1038/s41388-018-0362-5",
language = "English (US)",
pages = "1--10",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - β-catenin/TCF activity regulates IGF-1R tyrosine kinase inhibitor sensitivity in colon cancer

AU - Lee, Hani

AU - Kim, Nayoung

AU - Yoo, Young Ji

AU - Kim, Hyejin

AU - Jeong, Euna

AU - Choi, Seok Gyeong

AU - Moon, Sung Un

AU - Oh, Seung Hyun

AU - Mills, Gordon

AU - Yoon, Sukjoon

AU - Kim, Woo Young

PY - 2018/6/12

Y1 - 2018/6/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85048366358&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85048366358&partnerID=8YFLogxK

U2 - 10.1038/s41388-018-0362-5

DO - 10.1038/s41388-018-0362-5

M3 - Article

C2 - 29895971

AN - SCOPUS:85048366358

SP - 1

EP - 10

JO - Oncogene

JF - Oncogene

SN - 0950-9232

ER -