mTORC2 Phosphorylation of GSDME-N Drives Cullin4B-Mediated Proteasomal Degradation to Suppress Pyroptosis and Confer

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Qing-Qing Xu1,2,3,4, Ci-Ming Sun1,2,3, Sui-Xian Zhang1,2,3

  • 1State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|May 27, 2026
PubMed

Insights

Gasdermin E (GSDME) drives radiosensitivity in small cell lung cancer (SCLC). However, mTORC2 inhibits GSDME-mediated pyroptosis, promoting SCLC radioresistance and poor patient prognosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Radioresistance is a significant challenge in small cell lung cancer (SCLC) treatment, leading to therapeutic failure.
  • Identifying the molecular mechanisms underlying SCLC radioresistance is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To uncover novel molecular drivers of radiosensitivity in SCLC.
  • To elucidate the role of mTORC2 in SCLC radioresistance.
  • To investigate the interplay between mTORC2, GSDME, and pyroptosis in SCLC.

Main Methods:

  • Utilized an unbiased CRISPR screen to identify key regulators of radiosensitivity.
  • Investigated the mechanism of GSDME regulation by mTORC2, including phosphorylation and ubiquitination.
  • Analyzed clinical data to correlate mTORC2 levels with patient prognosis.

Main Results:

  • Identified Gasdermin E (GSDME) as a critical determinant of radiosensitivity in SCLC.
  • Demonstrated that mTORC2 promotes SCLC radioresistance by inhibiting GSDME-N-mediated pyroptosis.
  • Elucidated that mTORC2 phosphorylates GSDME-N, leading to its ubiquitination and proteasomal degradation via the CUL4B-RBBP4 complex.
  • Found elevated mTORC2 levels associated with unfavorable prognosis in SCLC patients.

Conclusions:

  • mTORC2 plays a key role in SCLC radioresistance by suppressing GSDME-mediated pyroptosis.
  • Targeting the mTORC2/GSDME pathway presents a potential therapeutic strategy to overcome SCLC radioresistance.
Keywords:
GSDMEmTORC2pyroptosisradioresistancesmall cell lung cancer

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