# Selective but not pan-CDK inhibition abrogates 5-FU-driven tissue factor upregulation in colon cancer

## TL;DR

This study shows that specific CDK inhibitors can reduce tissue factor levels and counteract chemotherapy-induced hypercoagulation in colon cancer.

## Contribution

The study identifies abemaciclib as a CDK inhibitor that reverses 5-FU-induced tissue factor upregulation and hypercoagulability in colon cancer.

## Key findings

- Low-dose chemotherapy increases tissue factor and induces a hypercoagulable state in CRC cells.
- Abemaciclib and palbociclib reduce tissue factor levels, while dinaciclib and THZ-1 increase it.
- Abemaciclib counteracts 5-FU-induced hypercoagulation and prolongs clotting times in CRC cells and human immune cells.

## Abstract

Thromboembolic events are complications in cancer patients and hypercoagulability has been linked to the tissue factor (TF) pathway, making this an attractive target. Here, we investigated the effects of chemotherapeutics and CDK inhibitors (CDKI) abemaciclib/palbociclib (CDK4/6), THZ-1 (CDK7/12/13), and dinaciclib (CDK1/2/5/9) alone and in combination regimens on TF abundance and coagulation. The human colorectal cancer (CRC) cell line HROC173 was treated with 5-FU or gemcitabine to stimulate TF expression. TF+ cells were sorted, recultured, and re-analyzed. The effect of treatment alone or in combination was assessed by functional assays. Low-dose chemotherapy induced a hypercoagulable state and significantly upregulated TF, even after reculture without treatment. Cells exhibited characteristics of epithelial-mesenchymal transition, including high expression of vimentin and mucin. Dinaciclib and THZ-1 also upregulated TF, while abemaciclib and palbociclib downregulated it. Similar results were observed in coagulation assays. The same anticoagulant activity of abemaciclib was seen after incubation with peripheral immune cells from healthy donors and CRC patients. Abemaciclib reversed 5-FU-induced TF upregulation and prolonged clotting times in second-line treatment. Effects were independent of cytotoxicity, senescence, and p27kip1 induction. TF-antibody blocking experiments confirmed the importance of TF in plasma coagulation, with Factor XII playing a minor role. Short-term abemaciclib counteracts 5-FU-induced hypercoagulation and eventually even prevents thromboembolic events.