2. Academic Validation
  3. Targeting PEA3 transcription factors to mitigate small cell lung cancer progression

Targeting PEA3 transcription factors to mitigate small cell lung cancer progression

  • Oncogene. 2022 Dec 13. doi: 10.1038/s41388-022-02558-6.
David W Shia 1 2 3,  WooSuk Choi 1,  Preethi Vijayaraj 1,  Valarie Vuong 1,  Jenna M Sandlin 1,  Michelle M Lu 1,  Adam Aziz 1,  Caliope Marin 1,  Cody J Aros 1 2 3,  Chandani Sen 1,  Abdo Durra 1,  Andrew J Lund 1 2,  Arunima Purkayastha 1,  Tammy M Rickabaugh 1,  Thomas G Graeber 4 5 6,  Brigitte N Gomperts 7 8 9 10
Affiliations

Affiliations

  • 1 UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
  • 2 Department of Molecular Biology Interdepartmental Program, University of California, Los Angeles, CA, 90095, USA.
  • 3 UCLA Medical Scientist Training Program, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
  • 4 Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, University of California, Los Angeles, CA, 90095, USA.
  • 5 Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, 90095, USA.
  • 6 Eli and Edythe Broad Stem Cell Research Center, University of California, Los Angeles, CA, 90095, USA.
  • 7 UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA. bgomperts@mednet.ucla.edu.
  • 8 Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, 90095, USA. bgomperts@mednet.ucla.edu.
  • 9 Eli and Edythe Broad Stem Cell Research Center, University of California, Los Angeles, CA, 90095, USA. bgomperts@mednet.ucla.edu.
  • 10 Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA. bgomperts@mednet.ucla.edu.
PMID: 36509998 DOI: 10.1038/s41388-022-02558-6
Abstract

Small cell lung Cancer (SCLC) remains a lethal disease with a dismal overall survival rate of 6% despite promising responses to upfront combination chemotherapy. The key drivers of such rapid mortality include early metastatic dissemination in the natural course of the disease and the near guaranteed emergence of chemoresistant disease. Here, we found that we could model the regression and relapse seen in clinical SCLC in vitro. We utilized time-course resolved RNA-sequencing to globally profile transcriptome changes as SCLC cells responded to a combination of cisplatin and etoposide-the standard-of-care in SCLC. Comparisons across time points demonstrated a distinct transient transcriptional state resembling embryonic diapause. Differential gene expression analysis revealed that expression of the PEA3 transcription factors ETV4 and ETV5 were transiently upregulated in the surviving fraction of cells which we determined to be necessary for efficient clonogenic expansion following chemotherapy. The FGFR-PEA3 signaling axis guided the identification of a pan-FGFR inhibitor demonstrating in vitro and in vivo efficacy in delaying progression following combination chemotherapy, observed inhibition of phosphorylation of the FGFR adaptor FRS2 and corresponding downstream MAPK and PI3K-Akt signaling pathways. Taken together, these data nominate PEA3 transcription factors as key mediators of relapse progression in SCLC and identify a clinically actionable small molecule candidate for delaying relapse of SCLC.

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  • HY-15391
    98.94%, VEGFR/FGFR抑制剂
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