Proteogenomic characterization of small cell lung cancer identifies biological insights and subtype-specific therapeutic strategies

Qian Liu, Jing Zhang, Chenchen Guo, Mengcheng Wang, Chenfei Wang, Yilv Yan, Liangdong Sun, Di Wang, Lele Zhang, Huansha Yu, Likun Hou, Chunyan Wu, Yuming Zhu, Gening Jiang, Hongwen Zhu, Yanting Zhou, Shanhua Fang, Tengfei Zhang, Liang Hu, Junqiang LiYansheng Liu, Hui Zhang, Bing Zhang, Li Ding, Ana I. Robles, Henry Rodriguez, Daming Gao, Hongbin Ji, Hu Zhou, Peng Zhang

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

We performed comprehensive proteogenomic characterization of small cell lung cancer (SCLC) using paired tumors and adjacent lung tissues from 112 treatment-naive patients who underwent surgical resection. Integrated multi-omics analysis illustrated cancer biology downstream of genetic aberrations and highlighted oncogenic roles of FAT1 mutation, RB1 deletion, and chromosome 5q loss. Two prognostic biomarkers, HMGB3 and CASP10, were identified. Overexpression of HMGB3 promoted SCLC cell migration via transcriptional regulation of cell junction-related genes. Immune landscape characterization revealed an association between ZFHX3 mutation and high immune infiltration and underscored a potential immunosuppressive role of elevated DNA damage response activity via inhibition of the cGAS-STING pathway. Multi-omics clustering identified four subtypes with subtype-specific therapeutic vulnerabilities. Cell line and patient-derived xenograft-based drug tests validated the specific therapeutic responses predicted by multi-omics subtyping. This study provides a valuable resource as well as insights to better understand SCLC biology and improve clinical practice.

Original languageEnglish
Pages (from-to)184-203.e28
JournalCell
Volume187
Issue number1
DOIs
StatePublished - Jan 4 2024

Keywords

  • HMGB3
  • ZFHX3 mutation
  • lung cancer
  • mass spectrometry
  • phosphoproteomics
  • precision treatment
  • proteogenomics
  • proteomics
  • small cell lung cancer
  • tumor subtyping

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