Work

ARID1A deficiency activates OSM-STAT3 axis in endometrial cancer, creating vulnerability to JAK/STAT3 inhibition

Year: 2026

Type: article

Abstract: ARID1A, a key component of the SWI/SNF chromatin remodeling complex, is a tumor suppressor frequently inactivated in many cancer types, including endometrial cancer.Exploiting ARID1A deficiency has emerged as a therapeutic strategy in these types of cancer.We here employed a synthetic lethal drug screen for ARID1A and found that JAK/STAT3 pathway is a therapeutic vulnerability in ARID1A-deficient endometrial cancer.Inhibition of JAK/STAT3 selectively inhibited the growth of ARID1A deficient endometria cancer cells in vitro and in a mouse xenograft tumor model.Mechanistically, ARID1A deficiency activates JAK/STAT3 signaling through promoting the transcription of the pleiotropic cytokine Oncostatin M (OSM).Autocrine activation of JAK/STAT3 signal by OSM in ARID1A-deficient endometrial cancer cells promotes PLK1 levels, inducing mitotic abnormality.These cells are highly vulnerable to JAK/STAT3 and PLK1 inhibitors for mitotic arrest and death.ARID1A and OSM protein levels are inverse correlated in patients with endometrial cancer, where elevated OSM levels are associated with poor patient survival.Our study indicates that OSM-STAT3-PLK1 axis inhibition presents a new therapeutic approach for endometrial cancer with ARID1A loss.

Source: International Journal of Biological Sciences

DOI: 10.7150/ijbs.129142