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

Li-Jie Chen1, Changxiang Shi2, Eun Ju Yang1

  • 1Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China.

International Journal of Biological Sciences
|March 9, 2026
PubMed

Insights

Loss of ARID1A in endometrial cancer creates a vulnerability in the JAK/STAT3 pathway. Inhibiting this pathway, along with OSM and PLK1, offers a novel therapeutic strategy for ARID1A-deficient tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • ARID1A is a tumor suppressor frequently inactivated in endometrial cancer.
  • Targeting ARID1A deficiency is a promising therapeutic strategy.
  • The SWI/SNF complex component ARID1A plays a critical role in tumor suppression.

Purpose of the Study:

  • To identify therapeutic vulnerabilities in ARID1A-deficient endometrial cancer.
  • To investigate the role of the JAK/STAT3 pathway in ARID1A-deficient endometrial cancer.
  • To explore novel therapeutic targets for endometrial cancer with ARID1A loss.

Main Methods:

  • Conducted a synthetic lethal drug screen for ARID1A.
  • Utilized in vitro cell culture and mouse xenograft models.
  • Analyzed protein and gene expression, including Oncostatin M (OSM) and PLK1 levels.

Main Results:

  • ARID1A deficiency activates JAK/STAT3 signaling via Oncostatin M (OSM) upregulation.
  • Inhibition of JAK/STAT3 selectively reduced ARID1A-deficient endometrial cancer cell growth.
  • OSM-STAT3-PLK1 axis activation leads to mitotic abnormalities and cell death in ARID1A-deficient cells.

Conclusions:

  • The OSM-STAT3-PLK1 axis is a key vulnerability in ARID1A-deficient endometrial cancer.
  • Targeting JAK/STAT3 and PLK1 presents a novel therapeutic approach.
  • Elevated OSM levels correlate with poor survival, highlighting its prognostic significance.
Keywords:
ARID1AOSM/STAT3/PLK1 axisendometrial cancersynthetic lethality

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