The transcription factor AP-1 as a treatment option for patients with colorectal adenocarcinoma

Background: The Activator Protein-1 (AP-1) transcription factors are expressed in many cancer entities and are correlated to deregulated transcription factor networks including dedifferentiation and therapy resistance. They are involved in key functions of the cellular biology and maintain and adjust the transcriptional networks leading to transformation and malignancy. Colorectal cancer is despite novel therapy approaches still one of the deadliest malignancies with a huge number of yearly cancers deaths. Especially once the primary tumor has spread, the overall survival of the patients is poor. There is an urgent need for better patient stratification to increase the outcome of the multimodally treated patients.

Material and Methods: A retrospective cohort of patients receiving colon, rectal or hepatic resection for colorectal cancer with and without multimodal approach was collected. The samples analyzed included primary and metastatic lesions and were used to analyze the expression of different AP-1 fators on mRNA and protein level. Furthermore, colorectal cancer cell lines as well as patient-derived organoids were used to knock-out single or combined AP-1 genes for downstream analysis like proliferation, survival and migration. Furthermore, pharmacological inhibition was performed and the survival over time was tested.

Results: Patients with a high AP-1 expression correlate to a reduced overall survival (OS) compared to patients with a low expression on mRNA level. This could be verified on protein level in a second cohort. Furthermore, we established cell lines and PDOs with single or combined double knock-out of AP-1 genes, which lead to decreased proliferation and survival of cell lines and PDOs. In addition, pharmacological inhibition could lead to growth arrest in a dose dependent matter in both cell lines and organoids.

Conclusion: This study suggests AP-1 as a biomarker to stratify patients with colorectal adenocarcinoma according to its expression level. The genetic or pharmacological inhibition might be a future treatment option for patients with strong AP-1 activity. Identifying those patients and adjusting the treatment might lead to better outcome.

Publication History

Article published online:
04 September 2025