Abstract C020: Quantitative measurements of functional activity of the TGFβ and MAPK-AP1 pathways in colon cancer provides information on their role in cancer development and metastasis

Abstract

Abstract Background: The advancement of targeted drugs for blocking tumor driving signaling pathway(s) is expected to lead to improved outcome for cancer patients. However, a critical requirement for that is reliable and accurate diagnostics on activity of oncogenic signaling pathways. A novel analysis method, based on Bayesian network-based inference of signaling pathway activity from levels of target gene mRNAs of the pathway-associated transcription factor, was developed to infer pathway activity from mRNA expression data [1], with which we previously reported that the WNT [1] and PI3K pathway [2] become active in colon carcinomas. Methods. Public datasets from the Gene Expression Omnibus, measured with the Affymetrix U133 Plus 2.0 platform, were analyzed for signaling pathway activity scores, among which are the MAPK-AP1, and TGFβ pathways. Colon tissue samples have been classified using the Consensus Molecular Subtypes of colorectal cancer classification (CMS). [3] Results. WNT and PI3K pathway activity were increased in colon carcinomas as reported before. The signaling pathway activity described by the CMS classification was confirmed using pathway activity analysis, TGFβ pathway activity was highest in the bad prognosis CMS4 subtype. A Kaplan-Meier curve shows higher TGFβ pathway activity to be associated with lower survival chance (p < 0.0001). Higher TGFβ pathway activity is seen in colon cancer metastases compared to primary tumors (p < 1e-13, based on 13 independent datasets). MAPK-AP1 pathway activity was increased (p < 1e-15, based on 18 analyzed datasets) in primary tumor samples compared to normal colon tissue, as demonstrated across multiple datasets, including a dataset with matched primary tumor and normal adjacent samples. Conclusion. MAPK-AP1 pathway activity in colon cancer is in line with frequent KRAS mutations that activate this pathway, while the dynamic range in activity may suggest a variation in sensitivity to targeted therapy. Results suggest that the lower survival associated with the CMS4 subtype is caused by increased TGFβ pathway activity, which is known to play a role in metastatic behavior, especially when activated in the presence of an active MAPK-AP1 signaling pathway, through interaction between the respective associated SMAD and c-Jun transcription factors [4]. Activity of these pathways can be measured simultaneously in a quantitative manner in an individual patient sample. They are clinically actionable and provide targets for drug-based therapy. Further clinical studies will be directed towards confirmation of the results and exploration of the clinical value of potential therapeutic approaches to prevent metastatic behavior in CRC on a personalized basis. References. [1] Cancer Res, vol. 74, no. 11, pp. 2936–2945, Jun. 2014. [2] The American Journal of Pathology, vol. 188, no. 9, pp. 1956–1972, Sep. 2018. [3] Nature Medicine, vol. 21, no. 11, pp. 1350–1356, Nov. 2015. [4] Cell, vol. 134, no. 2, pp. 215–230, Jul. 2008. Citation Format: Yvonne Wesseling-Rozendaal, Paul van Swinderen, Julie Gil, Sieglinde Neerken, Anja van de Stolpe. Quantitative measurements of functional activity of the TGFβ and MAPK-AP1 pathways in colon cancer provides information on their role in cancer development and metastasis [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C020. doi:10.1158/1535-7163.TARG-19-C020