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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
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Epidermal growth factor receptor cooperates with Src family kinases in acquired resistance to cetuximab

Deric L Wheeler1, Mari Iida, Tim J Kruser

  • 1Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. dlwheeler@wisc.edu

Cancer Biology & Therapy
|March 12, 2009
PubMed

Insights

Src family kinases (SFKs) drive resistance to cetuximab (an EGFR-blocking antibody) by enhancing EGFR activity. Inhibiting SFKs with dasatinib resensitized resistant cells, suggesting combination therapy for EGFR-refractory cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Epidermal growth factor receptor (EGFR) is crucial in oncogenesis.
  • Cetuximab, an EGFR inhibitor, benefits some metastatic colorectal cancer (mCRC) and head and neck squamous cell carcinoma (HNSCC) patients.
  • Most patients develop resistance to cetuximab therapy.

Purpose of the Study:

  • To investigate the role of Src family kinases (SFKs) in acquired cetuximab resistance.
  • To explore the mechanism by which SFKs contribute to EGFR signaling in resistant cells.
  • To evaluate the efficacy of combining cetuximab with an SFK inhibitor.

Main Methods:

  • Utilized cetuximab-resistant non-small cell lung cancer (NSCLC) cell line NCI-H226.
  • Assessed EGFR, HER3, and PI(3)K/Akt signaling pathways.
  • Investigated the effect of the Src kinase inhibitor dasatinib on signaling and cetuximab sensitivity.

Main Results:

  • Cetuximab-resistant cells exhibited increased EGFR expression and activity, leading to HER3 and downstream signaling hyper-activation.
  • SFKs were highly activated in resistant cells, enhancing EGFR's activation of HER3 and PI(3)K/Akt.
  • Dasatinib treatment decreased HER3 and PI(3)K/Akt activity and resensitized cells to cetuximab.

Conclusions:

  • SFKs and EGFR cooperate in the development of acquired resistance to cetuximab.
  • Targeting both EGFR and SFKs may represent a viable clinical strategy for overcoming cetuximab resistance.
  • Combination therapy warrants investigation in patients with acquired resistance to cetuximab.

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