UCN-01 enhances cytotoxicity of irinotecan in colorectal cancer stem-like cells by impairing DNA damage response

Colorectal cancer (CRC) is among the most prevalent and lethal cancers globally. Despite advancements in treatment, the prognosis for advanced-stage CRC remains poor, primarily due to recurrence and metastasis. Recent evidence attributes the high morbidity and mortality of CRC to a small subset of tumor cells known as cancer stem cells (CSCs). These cells possess tumor-initiating capacity, play a critical role in cancer recurrence and metastasis, and are resistant to current therapies.

To address this challenge, we screened CRC-derived CSCs in vitro using a library of protein kinase inhibitors. Our findings demonstrated that CRC-CSCs are resistant to targeted inhibition of key signaling pathways involved in cell survival and proliferation. However, broad-spectrum inhibition with the staurosporine derivative UCN-01 effectively suppressed CRC-CSC growth and enhanced the activity of irinotecan in both in vitro and in vivo models derived from CRC-CSCs.

Reverse-phase protein microarray (RPPA) analysis revealed that while CRC-CSCs exhibit distinct phospho-proteomic profiles, their sensitivity to UCN-01 depends on its disruption of the DNA damage response, specifically via Chk1 inhibition. Further studies showed that combining LY2603618, a selective Chk1/2 inhibitor, with irinotecan significantly reduced CRC-CSC growth in vivo. These results underscore the potential of irinotecan in combination with Chk1 inhibition as a promising therapeutic strategy for CRC treatment.