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Updated: Jun 2, 2025

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
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Catalytic-independent functions of the Integrator-PP2A complex (INTAC) confer sensitivity to BET inhibition

Pengyu Fan1,2, Xue-Ying Shang1, Aixia Song1

  • 1Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Medical Epigenetics, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.

Nature Chemical Biology
|January 14, 2025
PubMed

Insights

BET inhibitors show promise in cancer therapy, but resistance is common. This study reveals that the Integrator-PP2A complex (INTAC) auxiliary module is crucial for BET inhibitor efficacy by regulating H3K4 methylation, offering new therapeutic strategies.

Area of Science:

  • Epigenetics and Cancer Biology
  • Chromatin Regulation
  • Drug Resistance Mechanisms

Background:

  • Chromatin and transcription regulators are vital for cell identity and implicated in cancer.
  • BET proteins are promising therapeutic targets, but resistance limits their efficacy.
  • Mechanisms of resistance to BET inhibitors are not fully understood.

Purpose of the Study:

  • To identify factors mediating sensitivity and resistance to BET inhibitors.
  • To elucidate the role of the Integrator-PP2A complex (INTAC) in BET inhibitor response.
  • To explore strategies for overcoming BET inhibitor resistance.

Main Methods:

  • Genome-wide CRISPR screens were employed to identify genetic dependencies.
  • Investigated the interaction between INTAC and chromatin-modifying complexes.
  • Utilized targeted protein degradation to modulate histone methylation levels.

Main Results:

  • BET inhibitor efficacy depends on the auxiliary module of INTAC, independent of its catalytic activity.
  • INTAC's auxiliary module engages the RACK7/ZMYND8-KDM5C complex to remove H3K4 methylation.
  • Targeting WDR5 to reduce H3K4 methylation restored sensitivity to BET inhibitors in resistant cells.

Conclusions:

  • The auxiliary module of INTAC is a critical determinant of BET inhibitor sensitivity.
  • Simultaneous targeting of chromatin and transcription regulators can overcome drug resistance.
  • This provides a novel therapeutic strategy for BET inhibitor-resistant cancers.

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