Work

PTEN-deficient, chromosomal instability colorectal cancer is hypersensitive to STAT3 inhibition

Year: 2025

Type: article

Abstract: Genetic alterations that induce chromosomal instability (CIN) in colorectal cancer (CRC) cells result in partial impairments in a crucial cellular process, which present an opportunity for therapeutic exploitation in cancer treatment. In our effort to identify therapeutic vulnerability in PTEN-deficient CRC, we found that PTEN-deficient CRC cells exhibited elevated CIN phenotype and were hypersensitive to STAT3 inhibition. STAT3 inhibition induced a high level of abnormal spindle formation, causing mitotic arrest and death in PTEN-deficient CRC cells. Mechanistically, PTEN deficiency led to an increased phosphorylation in STAT3 and the hyperactivation of the downstream mitotic kinase PLK1, resulting in the formation of abnormal mitotic spindles and CIN. Inhibition of STAT3 strongly suppressed PLK1 phosphorylation in a STMN1-dependent manner, further inducing mitotic abnormalities in the cells. This irreparable mitotic defect triggered hyperactivation of the spindle assembly checkpoint and mitotic cell death in PTEN-deficient CRC cells. Collectively, our findings suggest that targeting STAT3-PLK1 axis represents a novel therapeutic approach for CRC cells with PTEN loss.

Source: International Journal of Biological Sciences

DOI: 10.7150/ijbs.111254