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

## TL;DR

This study shows that colorectal cancer cells lacking PTEN are highly sensitive to drugs that block STAT3, leading to cell death.

## Contribution

The study identifies a novel therapeutic vulnerability in PTEN-deficient colorectal cancer through the STAT3-PLK1 axis.

## Key findings

- PTEN-deficient CRC cells show elevated chromosomal instability and hypersensitivity to STAT3 inhibition.
- STAT3 inhibition causes abnormal spindle formation and mitotic arrest in PTEN-deficient CRC cells.
- Blocking STAT3 suppresses PLK1 phosphorylation and triggers mitotic cell death in these cells.

## 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.