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SYK-mediated epithelial cell state is associated with response to c-Met inhibitors in c-Met-overexpressing lung

Ji Zhou1,2, Xu-Chao Zhang3, Shan Xue4

  • 1Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.

Signal Transduction and Targeted Therapy
|May 14, 2023
PubMed

Insights

SYK regulates cell plasticity and sensitivity to c-Met inhibitors in non-small cell lung cancer (NSCLC). SYK overexpression identifies patients who benefit from c-Met inhibitor therapy, regardless of MET gene status.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Genomic MET alterations are known biomarkers for non-small cell lung cancer (NSCLC) patient stratification for c-Met inhibitor therapy, but clinical benefit remains limited.
  • C-Met protein overexpression occurs in 20-25% of NSCLC patients but is not yet a defined clinical biomarker for treatment decisions.
  • A need exists for improved strategies to accurately classify patients with c-Met overexpression for c-Met inhibitor treatment selection.

Purpose of the Study:

  • To investigate the role of SYK (Spleen Tyrosine Kinase) in regulating cell plasticity and sensitivity to c-Met inhibitors in NSCLC.
  • To determine if SYK can serve as a predictive biomarker for c-Met inhibitor response in NSCLC patients with c-Met overexpression.
  • To explore the mechanisms underlying resistance to c-Met inhibitors involving SYK and TGF-β1 signaling.

Main Methods:

  • In vitro and in vivo studies using patient-derived xenograft (PDX) models of NSCLC with c-Met overexpression.
  • Assessment of SYK's role in regulating epithelial-mesenchymal transition and sensitivity to c-Met inhibitors.
  • Analysis of clinical data correlating SYK and TGF-β1 expression with response to c-Met inhibitors in NSCLC patients.

Main Results:

  • SYK regulates cell plasticity and sensitivity to c-Met inhibitors, independent of MET gene status, in models with c-Met overexpression.
  • TGF-β1 treatment downregulates SYK, upregulates FRA1, and promotes a mesenchymal state, conferring resistance to c-Met inhibitors.
  • Clinically, NSCLC patients with both c-Met and SYK overexpression showed a 73.3% response rate to c-Met inhibitors, with longer progression-free survival.
  • SYK negativity combined with TGF-β1 positivity predicted de novo and acquired resistance to c-Met inhibitors.

Conclusions:

  • SYK plays a crucial role in maintaining the therapy-sensitive epithelial cell state in NSCLC.
  • SYK overexpression is a potential biomarker for precisely stratifying NSCLC patients with c-Met overexpression for c-Met-targeted therapy.
  • This finding expands the patient population predicted to benefit from c-Met inhibitor treatment, irrespective of specific MET alterations.

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