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Epithelioid sarcoma: from SMARCB1 loss to therapeutic vulnerabilities

Pawel Sobczuk1, Cristina Gómez-Palmero2, César Serrano1,3

  • 1Sarcoma Translational Research Group, Vall d'Hebron Institute of Oncology (VHIO).

Current Opinion in Oncology
|March 24, 2026
PubMed
Abstract

Insights

Epithelioid sarcoma (ES) is a rare cancer linked to SMARCB1 loss. While EZH2 inhibitors showed promise, resistance and side effects limit treatment options for this challenging soft tissue sarcoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Epithelioid sarcoma (ES) is an ultra-rare soft tissue sarcoma with incidence <0.5 new cases/million/year.
  • ES is defined by the loss of SMARCB1 expression, a key component of chromatin remodeling complexes.
  • This loss results in transcriptional dysregulation and dependency on the Polycomb Repressive Complex 2 (PRC2) and its enzyme EZH2.

Purpose of the Study:

  • To review the current therapeutic strategies for epithelioid sarcoma.
  • To explore recent advances in the molecular characterization of ES.
  • To identify potential novel treatment avenues for ES.

Main Methods:

  • Literature review of current therapeutic landscape and molecular advances in epithelioid sarcoma.
  • Analysis of molecular mechanisms underlying ES pathogenesis, including SMARCB1 loss and transcriptional changes.
  • Evaluation of therapeutic targets and treatment outcomes, including EZH2 inhibitors.

Main Results:

  • Loss of SMARCB1 in ES is primarily due to homozygous deletion on chromosome 22, leading to two distinct molecular subtypes.
  • Transcriptional analysis identified potential therapeutic targets such as MYC, mTOR, and TEK.
  • The EZH2 inhibitor tazemetostat was approved for advanced ES but faced challenges due to resistance mechanisms and secondary hematological malignancies.

Conclusions:

  • Treatment options for epithelioid sarcoma remain limited, with a poor prognosis despite advances in understanding its biology.
  • The rarity of ES hinders dedicated clinical trials and comprehensive molecular characterization.
  • Further research is essential to develop more effective therapies for this rare cancer.
Keywords:
SMARCB1epithelioid sarcomatazemetostat

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