Gefitinib and chemotherapy combination studies in five novel human non small cell lung cancer xenografts. Evidence linking EGFR signaling to gefitinib antitumor response

Int J Cancer. 2007 Apr 1;120(7):1579-90. doi: 10.1002/ijc.22364.

Abstract

The epidermal growth factor receptor (EGFR) signaling pathway is often activated in NSCLC, and thus represents a promising therapeutic target. We studied the antitumor activity of gefitinib (Iressa), an orally active EGFR-tyrosine kinase inhibitor, alone and in combination with standard chemotherapy in 5 recently established human NSCLC xenografts with wild-type EGFR. Mice were treated with 2 protocols of chemotherapy based on cisplatin (CDDP) combined with either gemcitabine (GEM) or vinorelbine (VNR). Gefitinib alone significantly inhibited tumor growth (TGI) in 4 of the 5 tumor xenografts (mean TGI of 58%, range: 25-70%). CDDP+VNR alone failed to achieve any significant responses, while CDDP+GEM achieved significant responses in 2 xenografts (TGI of 93 and 47%). Addition of gefitinib to CDDP+GEM potentialized chemotherapy in the 3 CDDP+GEM-resistant xenografts, but did not potentialize the CDDP+VNR combination. The effect of gefitinib treatment on the activity of extra cellular-regulated kinase (Erk), Akt, JNK and p38 kinases was assessed in IC9LC11 and IC1LC131, two NSCLC xenografts selected for their sensitivity and resistance to gefitinib, respectively. In IC9LC11, gefitinib strongly inhibited Erk, Akt and Jnk phosphorylation, but P38 remained active. Inversely, in IC1LC131, Erk and Akt pathways remained active, while Jnk and P38 pathways were inhibited by gefitinib. The data indicate that the antitumor activity of gefitinib in NSCLC, alone or in combination with chemotherapy, is tumor-dependent and is influenced by downstream signaling events independent of EGFR status.

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cisplatin / administration & dosage
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • ErbB Receptors / metabolism*
  • Gefitinib
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / metabolism
  • Maximum Tolerated Dose
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Quinazolines / administration & dosage
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction*
  • Survival Rate
  • Transplantation, Heterologous
  • Vinblastine / administration & dosage
  • Vinblastine / analogs & derivatives
  • Vinorelbine
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Quinazolines
  • RNA, Messenger
  • Deoxycytidine
  • Vinblastine
  • gemcitabine
  • ErbB Receptors
  • Receptor, ErbB-2
  • Proto-Oncogene Proteins c-akt
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Cisplatin
  • Vinorelbine
  • Gefitinib