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.

• Authors: Hani Lee, Nayoung Kim, Young Ji Yoo, Hyejin Kim, Euna Jeong, SeokGyeong Choi, Sung Un Moon, Seung Hyun Oh, Gordon B Mills, Sukjoon Yoon, Woo-Young Kim
• Journal: Oncogene (Oncogene) Vol. 37 Issue 40 Pg. 5466-5475 (10 2018) ISSN: 1476-5594 [Electronic] England
• PMID: 29895971 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• TCF Transcription Factors
• beta Catenin
• Receptor, IGF Type 1

Topics

• Cell Line, Tumor
• Colonic Neoplasms (drug therapy, pathology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Receptor, IGF Type 1 (antagonists & inhibitors)
• TCF Transcription Factors (metabolism)
• Transcription, Genetic (drug effects)
• Wnt Signaling Pathway (drug effects)
• beta Catenin (metabolism)