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Published on: February 10, 2022

SMARCB1 Deficiency in Tumors Confers a Vulnerability to H3K27 Demethylase Inhibitors via Autophagy Disruption

Andrea Vilarrubi1, Gabriela Guillén2, Xiaoyu Liu1

  • 1Josep Carreras Leukaemia Research Institute Badalona, Barcelona Spain.

Cancer Research
|June 10, 2026
PubMed

Insights

SMARCB1-deficient cancers, like malignant rhabdoid tumors, are sensitive to GSK-J4, a KDM6A/B inhibitor. Targeting this dependency offers a potential therapeutic strategy for SWI/SNF-mutant tumors.

Area of Science:

  • Oncology
  • Epigenetics
  • Cancer Biology

Background:

  • SWI/SNF complex inactivation is common in human cancers.
  • SMARCB1-deficient cancers exhibit unique epigenetic alterations and vulnerabilities.

Purpose of the Study:

  • To investigate the therapeutic potential of KDM6A/B inhibition in SMARCB1-deficient cancers.
  • To elucidate the mechanisms underlying sensitivity to KDM6A/B inhibitors in these tumors.

Main Methods:

  • Utilized cell lines and patient-derived xenograft models with SMARCB1 deficiency.
  • Assessed H3K27ac and H3K27me3 dynamics, autophagy, and endoplasmic reticulum stress responses.
  • Evaluated the efficacy of the KDM6A/B inhibitor GSK-J4.

Main Results:

  • SMARCB1-deficient cells showed sensitivity to GSK-J4, linked to aberrant H3K27ac/H3K27me3 dynamics.
  • Sensitivity was associated with elevated basal autophagy and increased susceptibility to ER stress.
  • GSK-J4 treatment suppressed tumor growth in preclinical models.
  • Restoring SMARCB1 abrogated sensitivity and promoted tumor adaptation mechanisms.

Conclusions:

  • SMARCB1-mutant cancers exhibit a specific dependency on H3K27 demethylase activity.
  • Targeting KDM6A/B with GSK-J4 presents a promising therapeutic avenue for SWI/SNF-deficient tumors, particularly MRTs.

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