Pharmacological targeting of the novel β-catenin chromatin-associated kinase p38α in colorectal cancer stem cell tumorspheres and organoids

The prognosis of locally advanced colorectal cancer (CRC) is currently unsatisfactory. This is mainly due to drug resistance, recurrence, and subsequent metastatic dissemination, which are sustained by the cancer stem cell (CSC) population. The main driver of the CSC gene expression program is Wnt signaling, and previous reports indicate that Wnt3a can activate p38 MAPK. Besides, p38 was shown to feed into the canonical Wnt/beta -catenin pathway. Here we show that patient-derived locally advanced CRC stem cells (CRC-SCs) are characterized by increased expression of p38 alpha and are addicted to its kinase activity. Of note, we found that stage III CRC patients with high p38 alpha levels display reduced disease-free and progression-free survival. Extensive molecular analysis in patient-derived CRC-SC tumorspheres and APC(Min/+) mice intestinal organoids revealed that p38 alpha acts as a beta -catenin chromatin-associated kinase required for the regulation of a signaling platform involved in tumor proliferation, metastatic dissemination, and chemoresistance in these CRC model systems. In particular, the p38 alpha kinase inhibitor ralimetinib, which has already entered clinical trials, promoted sensitization of patient-derived CRC-SCs to chemotherapeutic agents commonly used for CRC treatment and showed a synthetic lethality effect when used in combination with the MEK1 inhibitor trametinib. Taken together, these results suggest that p38 alpha may be targeted in CSCs to devise new personalized CRC treatment strategies.

Automated summary

Patients with locally advanced colorectal cancer (CRC) often have high levels of p38 alpha expression, which plays a crucial role in tumor proliferation, metastasis, and chemoresistance. Targeting p38 alpha with a kinase inhibitor like ralimetinib may sensitize CRC stem cells to chemotherapy, suggesting potential for personalized treatment strategies in CRC.